Protein tyrosine kinase inhibitors and their medical uses

Abstract

The present invention relates to protein tyrosine kinase inhibitors and their use in the prevention and / or treatment of hyperproliferative diseases mediated by protein tyrosine kinases, such as ocular diseases and malignant tumors associated with pathological neovascularization. In addition to effectively antagonizing VEGFR receptor tyrosine kinase activity, the protein tyrosine kinase inhibitors have improved pharmacokinetic properties and can highly selectively inhibit "off-target" EGFR tyrosine kinase activity, thereby reducing or avoiding adverse effects, particularly ocular side effects.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical technology, in particular to protein tyrosine kinase inhibitors and their medical uses, especially in the prevention and / or treatment of hyperproliferative diseases mediated by protein tyrosine kinases. [Background technology]

[0002] Receptor tyrosine kinases play important roles in developmental biology, tissue homeostasis, and cancer biology.

[0003] Receptor tyrosine kinases consist of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular catalytic domain. Dimerization of two receptor tyrosine kinases upon ligand binding leads to autophosphorylation of tyrosine residues in the intracellular catalytic domain, forming an active conformation and subsequently activating intracellular signaling cascades. Because of their important cellular effects, tyrosine kinases are highly regulated. When these kinases are constitutively activated by mutation or overexpression and are ligand-independent, many diseases, including cancer and ophthalmological diseases like diabetic retinopathy, develop through unregulated cell proliferation and other mechanisms. Therefore, tyrosine kinase inhibitors can pharmacologically treat several diseases by inhibiting this uncontrolled process. The development of inhibitors (RTKi) targeting proangiogenic receptor tyrosine kinases (mainly the vascular endothelial growth factor receptor (VEGFR) family) has significantly improved the prognosis of cancers such as renal cell carcinoma, hepatocellular carcinoma, and colorectal cancer, and has become an effective therapeutic approach for treating tumor-associated angiogenesis.

[0004] Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are leading causes of blindness worldwide. These pathologies are associated with neovascularization in the posterior part of the eye. DR, in particular, exhibits neovascular changes preferentially at the retinal level, whereas exudative AMD is characterized by neovascularization from the choroidal microvascular bed and invasion into the subretinal space. Both DR and AMD are characterized by endothelial cell (EC) proliferation and migration, increased vascular permeability, and inflammation. Vascular endothelial growth factor-A (VEGF-A) and its corresponding receptor (VEGFR) play critical roles in these processes. Many proliferative disorders, including ocular diseases, tumors, and cancers, involve the overexpression or upregulation of receptor tyrosine kinase (RTK) activity. Receptor tyrosine kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation typically results in functional changes of target proteins by altering their enzymatic activity, cellular localization, and binding to other proteins. Kinases are known to regulate most cellular pathways, especially those involved in signal transduction. To date, one approach to inhibiting the VEGF pathway is to inhibit receptor tyrosine kinase (RTK) activity. For ocular diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), the therapeutic goal of protein tyrosine kinase inhibitors is to eliminate pathological angiogenesis and disease progression, thereby preventing visual impairment. Furthermore, VEGFR, as a pro-angiogenic factor, plays a key role in tumor growth, invasion, and exudation, making it an excellent therapeutic target for many cancers. However, conventional VEGFR receptor tyrosine kinase inhibitors (RTKi) also suppress EGFR activity. This cross-reactivity can lead to side effects by inhibiting one or more biological functions at off-target receptors. This issue has a significant impact on the application of VEGFR receptor tyrosine kinase inhibitors for the treatment of ocular diseases. To date, the US FDA has not approved any small molecule tyrosine kinase inhibitors for the treatment of diabetic retinopathy or neovascular age-related macular degeneration. Summary of the Invention

[0005] The present invention provides compounds that inhibit VEGFR receptor tyrosine kinase activity while being selective for EGFR receptor tyrosine kinase inhibition in order to minimize side effects, particularly undesirable side effects in the eye, for use in the treatment of proliferative diseases or conditions mediated by protein tyrosine kinases, such as ocular diseases and malignancies associated with pathological angiogenesis.

[0006] To overcome the shortcomings of the prior art, the present invention provides protein tyrosine kinase inhibitors and their medical uses.

[0007] In a first aspect of the present invention, there is provided a compound having the structure:

[0008] [ka] (I) where: Ring A is a 5-7 membered heteroaryl ring; B ring is C6-C 10 an aryl ring or a 5- to 10-membered heterocyclic ring, 10 The aryl ring or 5- to 10-membered heterocycle is optionally C6-C 10 may be condensed with an aryl ring, a C5-C8 aliphatic ring, or a 5- to 10-membered heterocycle; X1 is O or S; Y is -N(C0-C 10 Alkyl group)(C0-C 10 alkyl group) or -O(C0-C 10 alkyl group), L1 is selected from a single bond, —C(O)—, —C(O)O—, —C(O)NR—, —C(O)N(R)O—, —S(O)—, —S(O)NR—, —S(O)—, —S(O)NR—, and —Cy-; -Cy- is selected from a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, and a substituted or unsubstituted heterocyclylene group; L2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently [ka] , -N(R4)-, -N(R4)C(O)-, -C(O)N(R4)-, -N(R4)S(O)2-, -S(O)2N(R4)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2, wherein a and b are each independently selected from an integer of 0 to 10, and R L201 and R L202 are each independently H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR L203 , -C(O)R L203 , -C(O)OR L203 , -NR L204 C(O)OR L203 , -OC(O)R L203 , -NR L204 SO2R L203 , -SO2NR L203 R L204 , -NR L204 C(O)R L203 , -C(O)NR L203 R L204 , -NR L203 R L204 , -SR L203 , -S(O)R L203 , -S(O)2R L203 , —SO3H, C3-C6 cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, wherein R L203 and R L204 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; L3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently [ka] , -N(R5)-, -N(R5)C(O)-, -C(O)N(R5)-, -N(R5)S(O)2-, -S(O)2N(R5)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O)2, , wherein c and d are each independently selected from an integer of 0 to 10, and R L301 and R L302 are each independently H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR L303 , -C(O)R L303 , -C(O)OR L303 , -NR L304 C(O)OR L303 , -OC(O)R L303 , -NR L304 SO2R L303 , -SO2NR L303 R L304 , -NR L304 C(O)R L303 , -C(O)NR L303 R L304 , -NR L303 R L304 , -SR L303 , -S(O)R L303 , -S(O)2R L303 , —SO3H, C3-C6 cycloalkyl group, cycloalkylalkyl group, heterocyclyl group, heterocyclylalkyl group, wherein R L303 and R L304 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; Each of R3 to R5 is independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group, wherein the alkyl group, the cycloalkyl group, and the heterocyclyl group are optionally selected from halogen, cyano, nitro, azido, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SON2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Silanyl group, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; R1 is one or more independent substituents on the B ring, and each R1 is independently H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NR 102 C(O)OR 101 , -OC(O)R 101 , -NR 102 SO2R 101 , -SO2NR 101 R 102 , -NR 102 C(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -S(O) j R 101 (where j is an integer from 0 to 2), -SO3H, -NR 102 (CR 103 R 104 )t OR 101 , -(CH2) t (C6-C 10 aryl group), -SO2(CH2) t (C6-C 10 aryl group), -S(CH2) t (C6-C 10 aryl group), -O(CH2) t (C6-C 10 aryl group), -(CH2) t (4-10 membered heterocyclyl group), -SO2(CH2) t (4-10 membered heterocyclyl group), -S(CH2) t (4-10 membered heterocyclyl group), -O(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 Cycloalkyl group), -SO2(CH2) t (C3-C 10 cycloalkyl group), -S(CH2) t (C3-C 10 cycloalkyl group), -O(CH2) t (C3-C 10 cycloalkyl) (wherein t is an integer of 0 to 5), wherein the C1-C 10 Alkyl groups, C6-C 10 The aryl group, the 4- to 10-membered heterocyclyl group may optionally be substituted with a halogen, a cyano group, a nitro group, an azide group, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SO2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Silanyl group, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; Each R 101 ~R 104are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, a C-C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SO2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Silanyl group, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valences permit); R0 is: H, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 001 , -C(O)R 001 , -C(O)OR 001 , -NR 002 C(O)OR 001 , -OC(O)R 001 , -NR 002 SO2R 001 , -SO2NR 001 R 002 , -NR 002 C(O)R 001 , -C(O)NR 001 R 002 , -NR 001 R 002 , -S(O) i R 002 (wherein i is an integer from 0 to 2), -SO3H, -NR 002 (CR003 R 004 ) t OR 001 , [ka] Selected from Here, the E ring is C6-C 10 an aryl ring or a 4- to 10-membered heterocyclic ring, 10 The aryl ring or 4-10 membered heterocycle is optionally C-C 10 may be condensed with an aryl ring, a C5-C8 aliphatic ring, or a 4-10 membered heterocycle; R2 is H, =O, C1-C 10 Alkyl groups, C2-C 10 Alkenyl groups, C2-C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 201 , -C(O)R 201 , -C(O)OR 201 , -NR 202 C(O)OR 201 , -OC(O)R 201 , -NR 202 SO2R 201 , -SO2NR 201 R 202 , -NR 202 C(O)R 201 , -C(O)NR 201 R 202 , -NR 201 R 202 , -S(O) i R 201 (where i is an integer from 0 to 2), -SO3H, -(CH2) j (C6-C 10 aryl group), -SO2(CH2) j (C6-C 10 aryl group), -S(CH2) j (C6-C 10 aryl group), -O(CH2) j (C6-C 10 aryl group), -(CH2) j (4-10 membered heterocyclyl group), -SO2(CH2) j(4-10 membered heterocyclyl group), -S(CH2) j (4-10 membered heterocyclyl group), -O(CH2) j (4-10 membered heterocyclyl group), -(CH2) j (C3-C 10 Cycloalkyl group), -SO2(CH2) j (C3-C 10 cycloalkyl group), -S(CH2) j (C3-C 10 cycloalkyl group), -O(CH2) j (C3-C 10 cycloalkyl groups) (wherein j is an integer of 0 to 5), wherein the C1-C 10 Alkyl groups, C6-C 10 The aryl group and the 4- to 10-membered heterocyclyl group may optionally be substituted with halogen, cyano, nitro, azido, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SO2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valences permit); Each R 001 ~R 004 are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, a C-C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SO2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C1-C10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Silanyl group, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; Each R 201 ~R 204 are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, a C-C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′S02R″, —SO2NR′R″, —NR′C(O)R″, —C(O)NR′R″, —NR′R″, —SR′, —SOR′, —S02R′, —S03H, C1-C 10 Alkyl groups, C1-C 10 Halogenated alkyl groups, C1-C 10 Silanyl group, C3-C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; R' and R'' are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group.

[0009] In some embodiments of the present invention, Y is —N(C—C 10 Alkyl group)(C0-C 10 alkyl group), such as -NH2, C1-C3 alkylamino group.

[0010] In some embodiments of the present invention, Y is —O(C 10alkyl groups), such as -OH, C1-C3 alkoxy groups.

[0011] Specifically, the A ring is a 5- or 6-membered aryl or heteroaryl ring, for example, the A ring is [ka] wherein Y1, Y2, and Y3 each independently represent O, S, N, or C(R A ) and R A is selected from H, halogen, substituted or unsubstituted alkyl, hydroxy, alkoxy, amino, alkylamino, cyano, and nitro groups; p is 0 or 1; and in some embodiments of the present invention, the A ring is [ka] ,especially [ka] is.

[0012] In certain embodiments of the present invention, [ka] The part is [ka] It has the following structure.

[0013] Specifically, R A is selected from H, halogen, C1-C3 alkyl group, hydroxy group, C1-C3 alkoxy group, amino group, C1-C3 alkylamino group, cyano group, and nitro group; in some embodiments of the present invention, R A is H.

[0014] In some embodiments of the present invention, [ka] The part is [ka] ,especially [ka] It has the following structure.

[0015] Specifically, ring B is a benzene ring or a 5- or 6-membered monocyclic heterocycle, and the benzene ring or the 5- or 6-membered monocyclic heterocycle may optionally be fused with a benzene ring, a C5-C8 aliphatic ring, or a 5- or 6-membered monocyclic heterocycle.

[0016] In some embodiments of the present invention, ring B is a benzene ring, a benzoaliphatic ring, a heterocycle (including a monocyclic heterocycle (particularly a 5- to 6-membered monocyclic heterocycle), or a bicyclic heterocycle (particularly a 9- to 11-membered bicyclic fused heterocycle)). In some embodiments of the present invention, the 5- to 6-membered monocyclic heterocycle is [ka] In some embodiments of the invention, the benzoaliphatic ring has the structure: [ka] In some embodiments of the present invention, the bicyclic heterocycle has the structure: [ka] It has the following structure.

[0017] specifically, [ka] The part is [ka] It may have the structure:

[0018] In some embodiments of the invention, the B ring is a benzene ring, for example: [ka] Part [ka] is.

[0019] In some other embodiments of the invention, the B ring is a monocyclic heterocycle, particularly a 5-6 membered monocyclic heterocycle, such as [ka] The part is [ka] It could be.

[0020] In some embodiments of the present invention, [ka] The part is [ka] where R 1b represents C1-C6 halogenated alkyl groups, cyano groups, nitro groups, azide groups, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10cycloalkyl groups), more specifically, R 1b represents C1-C6 halogenated alkyl groups, cyano groups, nitro groups, azide groups, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101 , -(CH2) t (4-8 membered heterocyclyl group), -(CH2) t (C3-C6 cycloalkyl group) (wherein t is an integer of 0 to 5), R 1c is H, F, C1-C6 alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups), R 1a , R 1d , R 1e is H, a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group), a halogen (e.g., F, Cl, Br, I), a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101, -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups), Each R 101 and R 102 and have the definitions given above.

[0021] Furthermore, R 1b are -CF3, -CHF2, -CH2F, [ka] Cyano group, nitro group, azide group, -OH, [ka] can be selected from.

[0022] In some preferred embodiments of the present invention, R 1b is -C(O)NR 101 R 102 where R 101 and R 102 are each independently H, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C4-C 10 It is selected from cycloalkylalkyl groups.

[0023] Furthermore, R 1a , R 1e may each independently be selected from H, halogen (e.g., F, Cl), and a C1-C3 alkyl group (e.g., a methyl group).

[0024] Preferably, R1c can be selected from H, F.

[0025] Furthermore, R 1d may be selected from H, halogen (e.g., F, Cl), C1-C3 alkyl group (e.g., methyl group).

[0026] In some preferred embodiments of the present invention, [ka] The part is [ka] It has the following structure.

[0027] In some other embodiments of the invention, the B ring is a bicyclic heterocycle, particularly a 9-11 membered bicyclic fused heterocycle, such as [ka] wherein the G ring is a 5- or 6-membered heterocycle, for example, [ka] Part [ka] It could be.

[0028] In some other embodiments of the invention, the B ring is a fused bicyclic ring, particularly a 9-11 membered fused bicyclic ring, such as [ka] wherein the F ring is a 5- or 6-membered carbocyclic or 5- or 6-membered heterocyclic ring, for example: [ka] The part is [ka] It could be.

[0029] Specifically, each R 101 ~R 104 are each independently H, a C1-C6 alkyl group (e.g., -CH3, [ka] ), C1-C6 halogenated alkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 hydroxy group-substituted alkyl groups (e.g., [ka] ), C1-C6 alkoxy-substituted alkyl groups (e.g., [ka] ), C1-C6 amino group-substituted alkyl groups (e.g., [ka] ), C1-C6 alkylamino group-substituted alkyl group (e.g., [ka] ), C3-C 10 Cycloalkyl groups (e.g., [ka] ), C4-C 10 Cycloalkylalkyl groups (e.g., [ka] ), substituted or unsubstituted 4-10 membered heterocyclyl groups (e.g., [ka] C1-C 10 Silanyl-substituted alkyl groups (e.g., [ka] ), C1-C 10 Silanyl groups (e.g., [ka] , [ka] ) can be selected from.

[0030] More specifically, each R 101 ~R 104 are each independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] Selected from.

[0031] Specifically, each R1 independently represents a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group), a halogen (e.g., F, Cl, Br, I), a C1-C6 halogenated alkyl group (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t(4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups) (wherein t is an integer of 0 to 5), specifically, the 4- to 10-membered heterocycle is a 4- to 6-membered heterocycle, for example, [ka] Specifically, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, for example: [ka] is.

[0032] In some embodiments of the present invention, R 102 is H.

[0033] More specifically, each R1 is independently a C1-C6 alkyl group, a halogen, a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101 , -(CH2) t (4-8 membered heterocyclyl group), -(CH2) t (C3-C6 cycloalkyl) (wherein t is an integer from 0 to 5), and R 101 represents a C1-C6 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group), a C1-C6 halogenated alkyl group (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), a C3-C6 cycloalkyl group (e.g., [ka] ), C4-C 10 Cycloalkylalkyl group ( [ka] ) can be selected from.

[0034] In some embodiments of the present invention, each R1 is independently selected from H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, [ka] , [ka] , [ka] , F, Cl, Br, I, cyano group, nitro group, azide group, -OH, [ka] Selected from.

[0035] In certain embodiments of the invention, R0 is [ka] is.

[0036] In some embodiments of the invention, the E ring is a 4-10 membered (e.g., 4, 5, 6, 7, 8, 9, 10 membered) heterocycle, particularly a 4-8 membered saturated heterocycle (including monocyclic, polycyclic, e.g., fused, spiro or bridged polycyclic), such as [ka] In particular, it is a 5-7 membered nitrogen-containing heterocycle, for example: [ka] is.

[0037] In some embodiments of the present invention, [ka] The part is [ka] is.

[0038] Specifically, each R 201 ~R 204 are each independently H, a C1-C6 alkyl group (e.g., -CH3, [ka] ), C1-C6 halogenated alkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 hydroxy group-substituted alkyl groups (e.g., [ka] , [ka] , [ka] ), C1-C6 alkoxy-substituted alkyl groups (e.g., [ka] , [ka] , [ka] ), C1-C6 amino group-substituted alkyl groups (e.g., [ka] , [ka] , [ka] ), C1-C6 alkylamino group-substituted alkyl group (e.g., [ka] , [ka] , [ka] ), C3-C 10 Cycloalkyl groups (e.g., [ka] ), C4-C 10 Cycloalkylalkyl groups (e.g., [ka] ), substituted or unsubstituted 4-10 membered heterocyclyl groups (e.g., [ka] can be selected from.

[0039] More specifically, each R 201 ~R 204 are each independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] can be selected from.

[0040] Specifically, R2 is H, ═O, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, a cyano group, a nitro group, an azide group, -OR 201 , -C(O)R 201 , -C(O)OR 201 , -NHC(O)OR 201, -OC(O)R 201 , -NHSO2R 201 , -SO2NR 201 R 202 , -NHC(O)R 201 , -C(O)NR 201 R 202 , -NR 201 R 202 , -SR 201 , -S(O)2R 201 , -SO3H, -(CH2) j (phenyl group), -(CH2) j (4-10 membered heterocyclyl group), -(CH2) j (C3-C 10 cycloalkyl groups) (wherein j is an integer of 0 to 5), specifically, the 4- to 10-membered heterocycle is a 4- to 6-membered heterocycle, for example, [ka] Specifically, the C3-C 10 The cycloalkyl group is a C3-C6 cycloalkyl group, for example: [ka] is.

[0041] More specifically, R2 is H, ═O, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, a cyano group, a nitro group, an azido group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C 10 The alkyl group may be selected from cycloalkyl groups.

[0042] In some embodiments of the present invention, R2 is H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] F, Cl, Br, I, cyano group, nitro group, azide group, hydroxy group, methoxy group, ethoxy group, [ka] Selected from.

[0043] In some embodiments of the invention, R0 is selected from:

[0044] [ka] In certain embodiments of the invention, R is -NR 001 R 002 where R 001 and R 002 are each independently H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 hydroxy-substituted alkyl group, a C1-C6 alkoxy-substituted alkyl group, a C1-C6 amino-substituted alkyl group, a C1-C6 alkylamino-substituted alkyl group, a C3-C6 cycloalkyl group, a C4-C 10 It is selected from cycloalkylalkyl groups.

[0045] Specifically, R 001 and R 002 are each independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] Selected from.

[0046] In some embodiments of the invention, R0 is [ka] Selected from.

[0047] In some other embodiments of the present invention, R is H, a cyano group, —O(C—C 10 alkyl group), -O(C1-C 10 silanyl group), -S(C0-C 10 alkyl group), -C(O)(C0-C 10 alkyl group), -C(O)O(C0-C 10alkyl group), -OC(O)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)SO2(C0-C 10 alkyl group), -SO2N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)C(O)(C0-C 10 alkyl group), -C(O)N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -SO2(C0-C 10 alkyl group), wherein the alkyl group is optionally substituted by a group selected from halogen, cyano group, hydroxy group, amino group, C1-C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, for example, R0 is H, cyano group, -OH, [ka] is substituted by a group selected from

[0048] Specifically, R3 to R5 are each independently H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy-substituted alkyl group, a C1-C6 alkylamino-substituted alkyl group, a C3-C6 cycloalkyl group, a C4-C 10 More specifically, R3 to R5 are each independently selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, and a cyclobutyl group.

[0049] In some embodiments of the invention, R3 is H.

[0050] In some embodiments of the present invention, R4 is H.

[0051] In some embodiments of the present invention, R5 is H.

[0052] Specifically, -Cy- is [ka] can be selected from Each R 10 are each independently H, halogen, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 alkoxy-substituted alkyl group, a C1-C6 alkylamino-substituted alkyl group, a C3-C6 cycloalkyl group, a C4-C 10 cycloalkylalkyl groups, and 4- to 10-membered heterocyclyl groups, more specifically, each R 10 are each independently selected from H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, and a cyclobutyl group.

[0053] In a particular embodiment of the invention, L1 is -C(O)NR3-, wherein R3 has the above definition of the invention.

[0054] In some embodiments of the invention, L1 is -C(O)NH-.

[0055] In another particular embodiment of the invention, L1 is -Cy-, wherein -Cy- has the above definition of the invention.

[0056] In some embodiments of the invention, -Cy- is [ka] Selected from.

[0057] In other particular embodiments of the invention, L1 is a single bond.

[0058] In other particular embodiments of the invention, L1 is -C(O)-.

[0059] Specifically, for the definition of L2, a and b are each independently selected from 0, 1, 2, 3, 4, and 5.

[0060] Specifically, for the definition of L2, R L203 and RL204 are each independently H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azide group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C 10 The alkyl group may be selected from cycloalkyl groups.

[0061] Specifically, L2 is a single bond or C2-C 10 an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from —N(R4)—, —N(R4)C(O)—, —C(O)N(R4)—, —N(R4)S(O)2—, —S(O)2N(R4)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)2, and wherein one or more H atoms in the alkylene group are optionally independently replaced by H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azide group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 10 More specifically, L2 is a C2-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-.

[0062] In some embodiments of the invention, L2 is a single bond, [ka] Selected from.

[0063] Specifically, for the definition of L3, c and d are each independently selected from 0, 1, 2, 3, 4, and 5.

[0064] Specifically, for the definition of L3, R L303 and R L304are each independently H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azide group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C 10 The alkyl group may be selected from cycloalkyl groups.

[0065] Specifically, L3 is a C1-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, and wherein one or more H atoms in the alkylene group are optionally independently replaced by H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azide group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 cycloalkyl group, a C4-C6 cycloalkyl group, a C5-C6 cycloalkyl group, a C6-C6 cycloalkyl group, a C7-C6 cycloalkyl group, a C8-C6 cycloalkyl group, a C9-C6 cycloalkyl group, a C1 ... 10 Substituted by a group selected from a cycloalkylalkyl group, in some embodiments of the invention, L3 is a methylene group (-CH2-).

[0066] In certain embodiments of the invention, the compound has the structure:

[0067] [ka] (II) In certain embodiments of the invention, the compound has the structure:

[0068] [ka] (III) where R 11 is C1-C 10 It is an alkyl group.

[0069] Specifically, R 11 is a C1-C6 alkyl group, particularly a C1-C3 alkyl group, such as a methyl group or an ethyl group.

[0070] In some embodiments of the invention, the compound has the structure:

[0071] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] In a second aspect of the present invention, there are provided pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compounds according to the first aspect.

[0072] In some embodiments of the invention, the stereoisomer has the following structure:

[0073] [ka] [ka] [ka] In a third aspect of the present invention, Y in the first aspect of the present invention is -N(C0-C 10 Alkyl group)(C0-C 10The present invention provides an intermediate compound that can be used in the preparation of a compound (e.g., a compound represented by Formula II) that is a methyl group (alkyl group), the intermediate compound having the structure:

[0074] [ka] (IV) where R 12 is an alkyl group, Ring A, ring B, X1, L1, L2, L3, R1, R0, and m have the definitions set forth in the first aspect of the present invention.

[0075] Specifically, R 12 is a C1-C6 alkyl group, particularly a C1-C3 alkyl group, such as a methyl group or an ethyl group.

[0076] In certain embodiments of the invention, the intermediate compound has the structure:

[0077] [ka] (V) Specifically, the intermediate compound of formula V undergoes a one-step ammonolysis (eg, by reaction with an alcoholic solution of ammonia or aqueous ammonia) to give the compound of formula II.

[0078] In a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0079] Specifically, the pharmaceutically acceptable additive may be selected from one or more of a disintegrant, a binder, a lubricant, a suspending agent, a stabilizer, a filler, an absorption enhancer, a surfactant, a flavoring agent, an antioxidant, a preservative, and the like.

[0080] Specifically, in the pharmaceutical composition, the compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof may be used alone or in combination with other types of active ingredients.

[0081] Specifically, the pharmaceutical composition may be administered by any suitable route, such as a gastrointestinal route (e.g., oral administration, sublingual administration, rectal administration) or a non-gastrointestinal route (e.g., intravenous administration, intramuscular administration, intranasal administration, intraocular administration, intracerebral administration, intravaginal administration, intraperitoneal administration, transdermal administration, subcutaneous administration, intradermal administration, respiratory administration, etc.). In some embodiments of the present invention, the pharmaceutical composition may be administered by an intraocular route (e.g., eye drops, eye ointment, subconjunctival injection, intraocular injection).

[0082] Specifically, the pharmaceutical composition may be in any suitable dosage form, including, but not limited to, gastrointestinal dosage forms, gastrointestinal dosage forms, and parenteral dosage forms, such as injections (e.g., subcutaneous, intravenous, intramuscular, and intraperitoneal), respiratory dosage forms such as sprays, aerosols, and powder mists, dermal dosage forms such as topical solutions, lotions, ointments, plasters, pastes, patches, and patches, mucosal dosage forms such as eye drops, eye ointments, nasal drops, mouthwashes, and sublingual tablets, and intracavity dosage forms such as suppositories, aerosols, effervescent tablets, drops, and drop pills for use in the rectum, vagina, urethra, nose, and ear canal.

[0083] In some embodiments of the present invention, the pharmaceutical composition may be an ophthalmic formulation such as eye drops, eye ointment, and the like.

[0084] Specifically, each dosage form of the pharmaceutical composition can be prepared according to conventional manufacturing methods in the pharmaceutical field, for example, by mixing the active ingredient with one or more pharmaceutically acceptable additives and then preparing it into a desired dosage form.

[0085] Specifically, in the pharmaceutical composition, the weight proportion of the compound of the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound may be 0.1 to 99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, particularly 1 to 30%.

[0086] In a fifth aspect of the invention there is provided the use of a compound according to the first aspect, or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds thereof, in the preparation of a medicament for inhibiting protein tyrosine kinase activity.

[0087] Specifically, the protein tyrosine kinase may be VEGFR, EGFR, or TIE2, and particularly inhibits VEGFR activity.

[0088] Specifically, the agent is an agent that selectively inhibits VEGFR.

[0089] In a sixth aspect of the present invention there is provided the use of a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, in the preparation of a medicament for the prevention and / or treatment of a hyperproliferative disease mediated by a protein tyrosine kinase.

[0090] In a particular embodiment of the present invention, the disease is a tumor, particularly a malignant tumor (cancer), including but not limited to breast cancer, lung cancer (particularly non-small cell lung cancer), adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, myeloid metaplasia of unknown cause, mesothelioma, myelodysplastic syndrome, and hematopoietic malignancies.

[0091] Specifically, hematopoietic malignancies include leukemia, lymphoma, and multiple myeloma (MM).

[0092] Specifically, the leukemia can be chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute monocytic leukemia.

[0093] Specifically, lymphomas include Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic lymphoma (IMLL), and leukemia-associated lymphoma (LEM). The tumor may be a myeloid leukemia, precursor B-lymphoblastic lymphoma, primary central nervous system (CNS) lymphoma, T-cell NHL, precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous lipid membrane inflammatory T-cell lymphoma, anaplastic large cell lymphoma, NK / T-cell lymphoma, and in particular, diffuse large B-cell lymphoma (DLBCL). Specifically, in the use, tumor treatment includes killing tumors and preventing the metastatic spread of tumors and the growth of micrometastases.

[0094] In certain embodiments of the invention, the disease is an ocular disease, and is selected from the group consisting of diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema), age-related macular degeneration (AMD) (including neovascular (exudative) AMD, non-exudative AMD, and geographic atrophy), pathological choroidal neovascularization (CNV) resulting from any pathological mechanism (i.e., severe myopia, trauma, sickle cell anemia, ocular histoplasia, etc.), and the like. These conditions include, but are not limited to, retinal ocular dystrophies, pathologic subretinal neovascularization due to any pathologic mechanism (i.e., sickle cell retinopathy, Eales' disease, ocular ischemia, internal carotid artery cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative microarteritis, birdshot retino choroidopathy, 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.

[0095] In some embodiments of the invention, the disease is diabetic retinopathy, including simple (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema.

[0096] In some other embodiments of the invention, the disease is age-related macular degeneration (AMD), including neovascular (exudative) AMD, non-exudative AMD, and geographic atrophy.

[0097] In a seventh aspect of the present invention, there is provided a method of inhibiting protein tyrosine kinase activity, comprising administering to a subject in need thereof a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, or a pharmaceutical composition according to the fourth aspect of the present invention.

[0098] Specifically, the protein tyrosine kinase may be VEGFR (e.g., VEGFR1, VEGFR2, VEGFR3), EGFR, TIE2, FGFR (e.g., FGFR1, FGFR2, FGFR3, FGFR4), or PDGFR (e.g., PDGFRA, PDGFRB), and particularly inhibits the activity of VEGFR (e.g., VEGFR2).

[0099] Specifically, the method is a method for selectively inhibiting VEGFR.

[0100] In particular, the subject may be a mammal, especially a human being.

[0101] Specifically, the method is carried out in vivo or in vitro.

[0102] In an eighth aspect of the present invention, there is provided a method for preventing and / or treating a hyperproliferative disease mediated by a protein tyrosine kinase, comprising administering to a subject in need thereof a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, or a pharmaceutical composition according to the fourth aspect of the present invention. Specifically, said disease is as described in the sixth aspect of the present invention.

[0103] In particular, the subject may be a mammal, especially a human being.

[0104] In a ninth aspect of the present invention, there is provided a method of inhibiting the formation of ocular neovascularization, retinal extravasation, comprising the step of administering to a subject in need thereof a compound according to the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or a pharmaceutical composition according to the fourth aspect of the present invention.

[0105] Specifically, the administration may be by any suitable method, particularly intraocular administration, such as eye drops, eye ointment, subconjunctival injection, or intraocular injection, particularly eye drops.

[0106] In particular, the subject may be a mammal, especially a human being.

[0107] The present invention provides a series of compounds that have the ability to inhibit anti-angiogenic tyrosine kinases and are highly selective for inhibiting EGFR tyrosine kinase activity, in addition to effectively antagonizing VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase activity, thereby effectively reducing or completely avoiding the occurrence of side effects, particularly ocular side effects (e.g., epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosion and / or corneal edema, keratitis), and has excellent application and research value. DETAILED DESCRIPTION OF THE INVENTION

[0108] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0109] As used herein, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group (also referred to herein as an "aliphatic ring" or "cycloalkyl") that is fully saturated or contains one or more unsaturated units, which is connected to the remainder of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and mixtures thereof, such as (cycloalkyl)alkyl groups, (cycloalkenyl)alkyl groups, and (cycloalkyl)alkenyl groups. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0110] The term "carbocycle" refers to a ring consisting only of carbon atoms, and can be classified into an aliphatic ring and an aromatic ring.

[0111] The term "alkyl group" refers to a straight-chain or branched hydrocarbon radical containing no unsaturated bonds and connected to the remainder of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. When an alkyl group is substituted with a cycloalkyl group, the corresponding designation is "cycloalkylalkyl," such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. When an alkyl group is substituted with an aryl group, the corresponding designation is "arylalkyl," such as benzyl, diphenylmethyl, or phenethyl. When an alkyl group is substituted with a heterocyclyl group, the corresponding name is "heterocyclylalkyl group." In the present invention, a CO alkyl group refers to H, i.e., C 0-10 The alkyl group is H and C 1-10 Contains an alkyl group.

[0112] The term "alkylene group" refers to a hydrocarbon group (divalent alkyl group) formed by the loss of two hydrogen atoms from an alkane molecule, which may be straight or branched, and which is connected to the remainder of the molecule by a single bond. As used herein, typical alkylene groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 The alkylene group is a single bond and a C 1-10 Contains an alkylene group.

[0113] The term "cycloalkyl group" refers to an alicyclic hydrocarbon, for example, containing 1 to 4 single and / or fused rings and 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, or adamantyl group.

[0114] The term "alkoxy group" refers to a substituent formed after the hydrogen in a hydroxy group is replaced by an alkyl group, and includes, for example, alkoxy groups containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, and butoxy.

[0115] The term "alkylamino group" refers to a substituent formed after one or more hydrogens in an amino group (-NH2) are replaced by an alkyl group, for example, an alkylamino group containing 1 to 10 carbon atoms, such as [ka] Examples include:

[0116] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0117] The term "halogenated alkyl group" refers to a group formed after one or more hydrogens in an alkyl group are replaced by a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), and includes, for example, -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, and -CH2CH2CH2-CF3.

[0118] The term "aryl group" refers to a monocyclic or polycyclic radical, including monocyclic and / or polycyclic radicals containing fused aryl groups, e.g., 1 to 3 monocyclic or fused rings and 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12The term "aryl group" refers to an aryl group containing 6-12 carbon ring atoms, and includes, for example, phenyl, naphthalenyl, biphenyl, indenyl, and the like.

[0119] The term "heterocyclyl group" refers to a 3- to 18-membered ring group containing 2 to 17 carbon atoms and 1 to 10 heteroatoms, selected from N, O, or S atoms. Heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or polycyclic, such as tetracyclic, ring systems, which can include fused (two rings share two ring atoms), spiro (two rings share one ring atom), or bridged (two rings share three or more ring atoms) systems (excluding linked rings). Heterocyclyl groups can be partially saturated (heteroaryl groups) or fully saturated (heterocycloalkyl groups). Suitable heteroaryl groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms, and the heteroaryl groups include coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrimidinyl, purinyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, Examples of groups include phenyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furadinyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzoxadiazole, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl groups.Suitable heterocycloalkyl groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms, and the heterocycloalkyl groups include, inclusively, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepinyl, oxazetanyl, thiamine, thiamine, thiamine-1, thiamine-2, thiamine-3, thiamine-4, thiamine-5, thiamine-6, thiamine-7, thiamine-8, thiamine-9, thiamine-10, thiamine-11, thiamine-12, thiamine-13, thiamine-14, thiamine-15, thiamine-16, thiamine-17, thiamine-18, thiamine-19, thiamine-19, thiamine-19, thiamine-19, thiamine-19, thiamine-19, thiamine-19, thiamine-20, thiamine-21, thiamine-22, thiamine-23, thiamine-24, thiamine-25, thiamine-26, thiamine-27, thiamine-28, thiamine-29 ... Examples of suitable aryl groups include pyrimyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizinyl.

[0120] The term "optionally substituted" group refers to halogen, -CN, -NO2, -OR', -NR'R'', -S(O)t-R', -S(O)t-NR'R'', -COR', -C(O)OR', -C(O)NR'R'', -C(O)N(R')OR'', -OC(O)R', -OC(O)NR'R'', -NR'C(O)R'', -N(R')C(O)NR'R', -N(R')C(NR')NR'R', -NR'-S(O)t-R', -NR'-S(O)t-NR'R', -N=S(O)R'R'', -S(NR')(O)R'', -N(R')CN, -P(O)(R')NR'R'', -P(O)(R')OR'' or -P(O)R'R'', C 1-6 Alkyl group, C 1-6 Halogenated alkyl groups, C 1-6 Alkenyl group, C 1-6 Alkynyl group, C 3-6 Cycloalkyl groups, C 4-10 Cycloalkylalkyl groups, C 6-10 Aryl group, C 6-10Aryl group alkyl group, C 3-8 Heterocyclyl group, C 3-8 and t is 0, 1, or 2; and each R' and R'' is independently selected from H, halogen, -CN, -NO2, an alkyl group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an arylalkyl group, a heterocyclyl group, and a heterocyclylalkyl group; or R' and R'' attached to the same nitrogen atom form a heterocycle together with the nitrogen atom.

[0121] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0122] The term "acid addition salts" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphonic acid, and the like, and salts derived from organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted streptoalkanoates, hydroxystreptoalkanoates, streptoalkane diacids, aromatic acid salts, aliphatic and aromatic sulfonates, for example, acetates, salicylates, caprates, stearates, oleates, hexanoates, malates, glycolates, ethanesulfonates, isethionates, and the like. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, octoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate, methanesulfonate, and also include amino acid salts such as arginate, gluconate, galacturonate, aspartate, glutamate, etc. Acid addition salts can be prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner. The term "base addition salt" refers to salts formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucosamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in the conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.

[0123] The term "stereoisomer" includes the existence of enantiomers, diastereomers, and geometric isomers. Some compounds of the present invention contain cyclic hydrocarbon groups optionally substituted at one or more carbon atoms, in which case all geometric forms, both cis and trans, and mixtures thereof, are all within the scope of the present invention.

[0124] The term "solvate" refers to the physical association of the compound of the present invention with one or more solvent molecules. The physical association includes varying degrees of ionic and covalent bonds, including hydrogen bonds. In certain cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate may be isolated. The solvate includes solvates that can be separated from the solution phase. Representative solvates include ethanolates, methanolates, etc.

[0125] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, have been replaced by a deuterium atom (D).

[0126] It should be understood that the abundance of natural isotopes in synthesized compounds varies depending on the origin of the chemicals used for synthesis. Therefore, the compounds of the present invention inherently contain small amounts of deuterated isotopes. Despite this variation, the concentrations of stable hydrogen and carbon isotopes at natural abundance are low and insignificant compared to the degree of stable isotope substitution in the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66: 15; Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0127] In the compounds of the present invention, atoms not designated as deuterium are present at their natural isotopic abundance. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it is understood that the position is hydrogen composed of an isotope at its natural abundance. Similarly, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," it is understood that the position has an abundance of water deuterium at least 3000 times higher than the natural abundance of deuterium (0.015%) (i.e., at least 45% deuterium incorporation).

[0128] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0129] In other embodiments, the isotopic enrichment factor of the compounds of the invention for each designated deuterium atom is at least 3500 (52.5% deuterium incorporation at each designated deuterium site), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0130] The term "isotopes" refers to substances whose chemical structure differs from a specific compound of this invention only in isotopic composition.

[0131] The term "prodrug" refers to forms of the compounds of Formula I, including acetal, ester, and zwitterionic forms, that are suitable for administration to a patient and effective for their intended purpose without undue toxicity, irritation, allergic response, etc. Prodrugs are transformed in the body to produce the parent compound, such as by hydrolysis in the blood.

[0132] Terms such as "patient" or "subject" are used interchangeably herein and refer to any animal or cells thereof treated according to the methods described herein, whether in vitro or in situ. Specifically, such animals include mammals, such as rats, mice, guinea pigs, rabbits, dogs, monkeys, and humans, particularly humans.

[0133] The term "treatment" refers to preventing, curing, reversing, attenuating, ameliorating, minimizing, suppressing, arresting and / or halting one or more clinical symptoms of a disease after the onset of the disease.

[0134] The term "prevention" refers to treatment to avoid, minimize, or make it more difficult for a disease to develop or progress before the disease has occurred.

[0135] The term "tumor" refers to an abnormal mass of tissue whose growth is faster than and uncoordinated with normal tissue. Tumors are classified as "benign" or "malignant" based on characteristics such as the degree of cellular differentiation (morphological and functional), growth rate, local invasion, and metastasis. Benign tumors are typically well differentiated, grow slower than malignant tumors, and are confined to the site of origin. Benign tumors also lack the ability to invade, invasive, or metastasize to distant sites. In some cases, certain "benign" tumors may subsequently become malignant, likely due to additional genetic changes in a subpopulation of the tumor's pathologically proliferating cells; these tumors are referred to as "premalignant tumors." Malignant tumors are typically poorly differentiated (anaplastic), characteristically rapidly growing, and associated with progressive invasion, invasion, and destruction of surrounding tissue. Malignant tumors also typically have the ability to metastasize to distant sites.

[0136] The term "carcinosis" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).

[0137] The term "protein tyrosine kinase inhibitor" refers to a molecule that reduces, inhibits, or reduces one or more biological activities of a protein tyrosine kinase. The inhibitory effect of a protein tyrosine kinase inhibitor does not necessarily indicate complete elimination of protein tyrosine kinase activity. Protein tyrosine kinase activity is reduced by a significant amount, e.g., by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, compared to a control.

[0138] Unless otherwise specified, numerical ranges expressed in the format "from x to y" or "xy" are understood to be inclusive of x and y. When multiple preferred ranges are described for a particular property in the format "from x to y" or "xy," it is understood that all ranges combining the different endpoints may also be considered.

[0139] Various publications, patents and published patent specifications cited herein, the disclosures of which are incorporated herein by reference in their entireties.

[0140] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are known as the most potent vascular permeability factor and endothelial-specific mitogen, and play important roles in endothelial cell proliferation, migration, and angiogenesis. Angiogenesis is an important mechanism in many physiological and pathological processes, contributing to endothelial cell proliferation, migration, and survival, leading to the formation of renal tubules, and ultimately promoting angiogenesis. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play important roles in pathological angiogenesis, including tumor progression and ocular neovascular diseases. For example, VEGF expression levels are significantly positively correlated with the degree of angiogenesis in tumor tissue. VEGF acts on VEGFR receptors to activate phosphorylation of VEGFR receptor tyrosine kinase, leading to aberrant cell signaling, thereby promoting endothelial cell proliferation and angiogenesis. VEGF is a major contributor to many cancers and ocular diseases associated with pathological neovascularization. However, despite efforts to design VEGFR receptor-specific molecules, cross-reactivity with other "off-target" receptors, such as the TIE2 receptor (i.e., TEK tyrosine kinase) and EGFR receptor activity, is inevitable. Receptor tyrosine kinase inhibitors inhibit EGFR simultaneously with VEGFR, which has been clinically confirmed to affect EGFR-mediated corneal epithelial wound healing and cause ocular side effects. TIE2 also plays an important role in maintaining vascular integrity. Its inhibition weakens endothelial cell adhesion, promoting fluid leakage and ocular edema, impairing retinal blood flow and oxygen supply, potentially leading to vision loss. The compounds of the present invention offer significant improvements in the selectivity of TIE2 and EGFR inhibition. Not only do they enhance the antagonism of all VEGFR receptor (VEGFR1, VEGFR2, and VEGFR3) tyrosine kinase activity, but they also significantly enhance the selectivity of TIE2 and EGFR receptor activity inhibition (see experimental examples).

[0141] VEGFR2 is the primary receptor for VEGF-induced endothelial cell signaling. Upon binding of the ligand VEGF to the receptor during development and / or after tissue injury, VEGFR2 undergoes autophosphorylation and activation, inducing angiogenesis and bypassing blocked blood vessels. Clinical therapies targeting the vascular endothelial growth factor (VEGF-A) / VEGFR2 signaling pathway have been shown to be effective in treating ocular neovascular diseases such as wet AMD. The compounds of the present application exhibit significant inhibitory activity against VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells, blocking abnormal cell signaling and thereby inhibiting neovascularization (see Experimental Examples). The primary function of signaling via the VEGFR receptor is to promote endothelial cell proliferation and neovascularization, and the compounds of the present application demonstrated the ability to inhibit VEGF-induced human endothelial cell proliferation at nanomolar concentrations (see Experimental Examples). In summary, the compounds of the present application are novel tyrosine kinase inhibitors. In addition to treating neovascular age-related macular degeneration and diabetic retinopathy, this new type of tyrosine kinase inhibitor can also be used in tumor adaptive therapy, where it inhibits the formation of new blood vessels in tumors, thereby cutting off the blood and nutrient supply necessary for tumor growth and leading to the death of tumor cells.

[0142] The U.S. Food and Drug Administration (FDA) has approved aflibercept (VEGF Trap-Eye) for the treatment of neovascular age-related macular degeneration and diabetic retinopathy. However, aflibercept is a 115 kDa fully human recombinant protein that must be administered via intravitreal injection. For clinicians and patients, frequent intravitreal injections are inconvenient and involve rare but serious injection-related risks (e.g., retinal detachment, endophthalmitis, intraocular inflammation, and cataracts), leading to many patients missing scheduled injections and reduced therapeutic efficacy. Our compound (a small molecule VEGFR tyrosine kinase inhibitor) offers an alternative to VEGF antibody biologics, demonstrating an alternative approach that directly targets VEGF. The role of the VEGF pathway in neovascular age-related macular degeneration and diabetic retinopathy has been demonstrated by favorable clinical results of VEGF antibody biologics. Small molecule VEGFR tyrosine kinase inhibitors offer numerous advantages over monoclonal antibodies. Their ability to inhibit all members of the VEGFR family allows them to effectively inhibit VEGF signaling. To avoid intravitreal injection, they can be formulated as eye drops, penetrating the cell membrane and directly interacting with the cytoplasmic domain of receptor tyrosine kinases (RTKs). Furthermore, the economic cost of small molecule eye drops is lower than that of monoclonal antibodies. The development of small molecule tyrosine kinase inhibitors for clinical use in age-related macular degeneration and diabetic retinopathy faces significant challenges. The most important challenge is overcoming the risk of off-target toxicity. Inhibiting VEGFRs in healthy vasculature can cause serious adverse events, such as hypertension, bleeding, and thrombosis. Despite numerous clinical successes in oncology therapy, the safety of oral VEGFR-2 inhibitors may be a major reason why their clinical administration and / or development in patients with age-related macular degeneration and diabetic retinopathy has been limited during clinical use. Therefore, compared to oral VEGFR-2 inhibitors, topical eye drops could provide an effective treatment that limits systemic exposure and avoids the issue of off-target toxicity.

[0143] While topical ocular administration has proven successful for treating anterior segment-related diseases (e.g., glaucoma), there are currently no FDA-approved topical therapies for posterior segment-related eye diseases (e.g., neovascular AMD, diabetic retinopathy). This is largely due to the anatomical and physiological barriers that the human eye has evolved to protect from foreign substances. The tear film is one of the first barriers that must be overcome. Compounds in the anterior segment are rapidly washed away by the tear film and excreted through the nasolacrimal duct, so compounds must be rapidly absorbed after topical instillation. However, absorption / penetration into ocular tissues can also be challenging. One absorption pathway involves penetration through the cornea, which is composed of tight junctions and an epithelium with alternating lipophilic and hydrophilic layers. Another absorption pathway involves penetration through the conjunctiva and subsequent diffusion into the sclera, a relatively permeable ocular tissue. However, because the conjunctiva is a highly vascularized tissue, drugs that enter the conjunctiva tend to be "lost" to the systemic circulation. Compounds exposed at the sclera can diffuse to the choroid, which is the primary target tissue for neovascular AMD. Diffusion from the choroid to the retina (a target tissue for neovascular AMD) is further attenuated through the blood-retinal barrier (BRB). The BRB functions similarly to the blood-brain barrier and may be a strong barrier to compound diffusion. It is estimated that less than 5% of a topical administered dose reaches posterior ocular tissues due to this anatomical and physiological barrier. Despite these challenges associated with topical administration, the present invention focuses on the structure-activity relationship (SAR) associated with ocular and blood exposure. Effective delivery to posterior ocular tissues can be achieved by compound-containing eye drops (see experimental examples). Rapid degradation of the compounds was observed in plasma, suggesting that the exposure of the compounds of the present invention to posterior ocular tissues is due to distribution through the infusion site and not derived from the systemic bloodstream. Meanwhile, low plasma or systemic exposure of these compounds is beneficial in avoiding systemic target toxicity. Furthermore, significant exposure was also observed in scleral tissue, suggesting that these compounds are effectively delivered to the posterior tissues of the eye (choroid and retina) primarily via the sclera.The compound showed some exposure in the posterior segment of the eye (choroid and retina) even 8 hours after administration. The present invention provides novel compounds that bind to relevant ocular target receptors, increase bioavailability in the posterior segment of the eye, and maintain sufficient drug concentrations in the posterior segment of the eye (such as the choroid and retina) to alleviate the problems associated with conventional topical therapeutic agent delivery to the eye.

[0144] One of the goals of medicinal chemistry is to improve the bioavailability and stability of compounds to enhance therapeutic efficacy. Bioavailability refers to the rate and extent to which a therapeutic agent is absorbed from a drug form and becomes available at the site of action. Conventional tyrosine kinase (e.g., VEGFR1, VEGFR2, and VEGFR3) inhibitors suffer from poor solubility and / or low kinase inhibitory activity, which significantly affect the bioavailability of these compounds and reduce their pharmacodynamic effects. The present invention provides compounds that may have the advantages of improved solubility and / or significant kinase inhibitory activity (see Test Examples). In addition, measurements have also provided the percentage of free drug of the compounds of the present invention, i.e., free from melanin and able to interact with receptors in ocular tissues (see Test Examples). Melanocytes in the eye are present in the retinal pigment epithelium, choroid, and ciliary body in the posterior segment of the eye, the anterior segment of the eye, and the iris. Binding of compounds to melanin may affect the ocular pharmacokinetics after topical administration. The present invention provides compound-containing eye drops for treating age-related macular degeneration and diabetic retinopathy. These diseases affect the posterior segment of the eye, and compound-containing eye drops are intended for effective delivery to posterior segment tissues. In these cases, drugs may bind strongly to melanin in the posterior segment (retinal pigment epithelium, choroid) or anterior segment (ciliary body, iris). Many clinical drugs bind to melanin, affecting their ocular pharmacokinetics. Compound-melanin binding is an important factor in ocular pharmacokinetics and pharmacodynamics and must be considered in drug discovery and development.

[0145] Many eye drops have limited permeability through the corneal and conjunctival barriers, which can necessitate high concentrations of the compound in ophthalmic formulations to achieve therapeutic levels effective in posterior segment tissues. Depending on the compound (either the molecule itself or at high concentrations), ophthalmic formulations can have adverse effects on anterior segment tissues (conjunctiva, cornea, and / or lens) and can cause damage to the ocular surface, such as corneal epithelial defects and erosions. Clinical evidence has shown that treatment with EGFR antibody drugs can cause ocular side effects, such as epithelial degeneration and defects, ulcers, thinning of the corneal epithelium, erosions and / or corneal edema, and keratitis. EGFR is a key factor in wound healing in human corneal epithelial cells. Therefore, it is necessary to select compounds for topical ophthalmic formulations that can avoid EGFR activity inhibition. The compounds of the present invention not only effectively antagonize VEGFR1, VEGFR2, and VEGFR3 tyrosine kinase activity, but also exhibit high selectivity for EGFR tyrosine kinase activity inhibition (see experimental examples). The inventors evaluated the maximum tolerated dose (MTD) of compounds administered by ophthalmic instillation in male Dutch-Belted rabbits to select the dose with the lowest toxicity and highest activity possible for in vivo animal efficacy studies. The maximum tolerated dose (MTD) on day 3 of ophthalmic instillation was 100 μg / eye for PAN90806 and 250 μg / eye or higher for T093. Furthermore, to evaluate the ocular toxicity risk of T093 and PAN90806, the inventors administered the compounds to rabbits for six consecutive days. No abnormalities were observed in the eyes of any rabbit in the T093 (250 μg / eye) group, but the MTD of the positive compound, PAN90806, was reduced to 50 μg / eye. T078 and T116 were administered at 1000 μg / eye for three consecutive days, and toxicity risk assessment revealed no abnormalities in the eyes of any rabbit. Therefore, the maximum tolerated dose (MTD) of T078 and T116 on day 4 of instillation was 1000 μg / eye or more.

[0146] The present invention provides compounds of formula I, particularly compounds of formula II and III, and medical uses thereof.

[0147] In a particular embodiment (1) of the present invention, in formula I, in particular in formula II and III, L is -C(O)NR- or a single bond, [ka] Part [ka] where R1 is a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl group) (where t is an integer from 0 to 5), and the E ring, R2, has the corresponding definition described in the present invention.

[0148] Specifically, R 101 and R 102 are each independently H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a C1-C6 hydroxy-substituted alkyl group, a C1-C6 alkoxy-substituted alkyl group, a C1-C6 amino-substituted alkyl group, a C1-C6 alkylamino-substituted alkyl group, a C3-C 10 Cycloalkyl groups, C4-C 10 cycloalkylalkyl groups, substituted or unsubstituted 4- to 10-membered heterocyclyl groups, [ka] , [ka] , C1-C 10 Silanyl-substituted alkyl groups, C1-C 10 The silanyl group may be selected from the group consisting of silanyl groups.

[0149] More specifically, each R 101 and R 102 are each independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] can be selected from.

[0150] In some embodiments of the present invention, each R 101 and R 102 are each independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] Selected from.

[0151] In some embodiments of the present invention, R 102 is H.

[0152] In some embodiments of the present invention, R 101 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] Selected from.

[0153] More specifically, R1 is a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR101 , -NHR 101 , -SR 101 , -(CH2) t (4-8 membered heterocyclyl group), -(CH2) t (C3-C6 cycloalkyl group) (wherein t is an integer of 0 to 5).

[0154] More specifically, R1 may further comprise a group selected from a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group), and a halogen (e.g., F, Cl, Br, I). In some embodiments of the present invention, L1 is -C(O)NR3- or a single bond; [ka] The part is [ka] where R1 is -CF3, -CHF2, -CH2F, [ka] , [ka] , [ka] , cyano group, nitro group, azide group, -OH, [ka] More specifically, R1 may also include a group selected from a C1-C6 alkyl group (e.g., a methyl group, an ethyl group, an n-propyl group, an isopropyl group), and a halogen (e.g., F, Cl, Br, I).

[0155] In some embodiments of the present invention, [ka] The part is [ka] where R 1b represents C1-C6 halogenated alkyl groups, cyano groups, nitro groups, azide groups, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups), more specifically, R 1b represents C1-C6 halogenated alkyl groups, cyano groups, nitro groups, azide groups, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101 , -(CH2) t (4-8 membered heterocyclyl group), -(CH2) t (C3-C6 cycloalkyl group) (wherein t is an integer of 0 to 5), R 1c is H, F, C1-C6 alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups), R 1a , R 1d , R 1e is H, a C1-C6 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group), a halogen (e.g., F, Cl, Br, I), a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups), Each R 101 and R 102 and have the definitions given above.

[0156] Furthermore, R 1b are -CF3, -CHF2, -CH2F, [ka] , [ka] , [ka] , cyano group, nitro group, azide group, -OH, [ka] can be selected from.

[0157] In some embodiments of the present invention, R 1b is -C(O)NR 101 R 102 where R 101 and R 102 are each independently H, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C4-C 10 It is selected from cycloalkylalkyl groups.

[0158] Furthermore, R 1a , R 1e may each independently be selected from H, halogen (e.g., F, Cl), and a C1-C3 alkyl group (e.g., a methyl group).

[0159] Furthermore, R 1c can be selected from H, F.

[0160] Furthermore, R 1d may be selected from H, halogen (e.g., F, Cl), C1-C3 alkyl group (e.g., methyl group).

[0161] In some embodiments of the present invention, [ka] The part is [ka] It has the following structure.

[0162] In some embodiments of the invention, L1 is -C(O)NR3- and R0 is [ka] is.

[0163] In some embodiments of the present invention, R is H, a cyano group, —O(C 10 alkyl group), -O(C1-C 10 silanyl group), -N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -S(C0-C 10 alkyl group), -C(O)(C0-C 10 alkyl group), -C(O)O(C0-C 10 alkyl group), -OC(O)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)SO2(C0-C 10 alkyl group), -SO2N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)C(O)(C0-C 10 alkyl group), -C(O)N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -SO2(C0-C 10 alkyl groups), wherein the alkyl groups are optionally substituted by halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl groups, more specifically, R0 is [ka] , H, cyano group, -OH, [ka] Selected from.

[0164] In some embodiments of the invention, L2 is C0-C10 an alkylene group, wherein one or more H atoms in the alkylene group are optionally independently selected from H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azido group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 10 It is substituted by a group selected from a cycloalkylalkyl group, more specifically, L2 is a C0-C6 alkylene group.

[0165] In some embodiments of the invention, L is a single bond, L is a single bond, and R is H, i.e., the compound is [ka] ,especially [ka] , [ka] having the structure [ka] has the definition given above.

[0166] In some embodiments of the invention, the compound has the following structure: [ka] [ka] [ka] [ka] [ka] [ka] In a particular embodiment (2) of the present invention, in formula I, particularly in formula II and III, L is -C(O)NR- and ring B is a monocyclic heterocycle, particularly a 5- or 6-membered monocyclic heterocycle, for example: [ka] The part is [ka] wherein R1 has the above definition of the present invention.

[0167] Specifically, each R1 is independently H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups) (wherein t is an integer of 0 to 5).

[0168] In some embodiments of the present invention, each R1 may be independently selected from H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, -OH, and a C1-C6 alkoxy group.

[0169] More specifically, each R1 is independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] , [ka] , [ka] , F, Cl, Br, I, cyano group, nitro group, azide group, -OH, [ka] can be selected from.

[0170] In some embodiments of the invention, L is —C(O)NR— and R is [ka] is.

[0171] In some embodiments of the present invention, R is H, a cyano group, —O(C 10 alkyl group), -O(C1-C 10 silanyl group), -N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -S(C0-C 10 alkyl group), -C(O)(C0-C 10 alkyl group), -C(O)O(C0-C 10 alkyl group), -OC(O)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)SO2(C0-C 10 alkyl group), -SO2N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)C(O)(C0-C 10 alkyl group), -C(O)N(C0-C 10Alkyl group)(C0-C 10 alkyl group), -SO2(C0-C 10 alkyl group), wherein the alkyl group is optionally substituted by a group selected from halogen, cyano group, hydroxy group, amino group, C1-C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, more specifically, R0 is [ka] Selected from.

[0172] In some embodiments of the invention, L2 is C0-C 10 an alkylene group, wherein one or more H atoms in the alkylene group are optionally independently selected from H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azido group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 10 It is substituted by a group selected from a cycloalkylalkyl group, more specifically, L2 is a C0-C6 alkylene group.

[0173] In some embodiments of the invention, the compound has the following structure: [ka] In a particular embodiment (3) of the present invention, in formula I, particularly in formulas II and III, L is -C(O)NR- and ring B is a bicyclic, particularly a 9-11 membered fused bicyclic ring, for example: [ka] The part is [ka] wherein R1 has the above definition of the present invention.

[0174] Specifically, each R1 is independently H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, a cyano group, a nitro group, an azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO2R 101 , -SO2NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O)2R 101 , -SO3H, -(CH2) t (phenyl group), -(CH2) t (4-10 membered heterocyclyl group), -(CH2) t (C3-C 10 cycloalkyl groups) (wherein t is an integer of 0 to 5).

[0175] In some embodiments of the present invention, each R1 may be independently selected from H, a C1-C6 alkyl group, a C1-C6 halogenated alkyl group, a halogen, -OH, and a C1-C6 alkoxy group.

[0176] More specifically, each R1 is independently H, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, -CF3, -CHF2, -CH2F, [ka] , [ka] , [ka] , F, Cl, Br, I, cyano group, nitro group, azide group, -OH, [ka] In some embodiments of the invention, each R is independently selected from H, a methyl group, an ethyl group, —CF, —CHF, —CHF, F, Cl, Br, I, a cyano group, a nitro group, an azide group, and —OH.

[0177] In some embodiments of the invention, L1 is -C(O)NR3- and R0 is [ka] is.

[0178] In some embodiments of the present invention, R is H, a cyano group, —O(C 10 alkyl group), -O(C1-C 10 silanyl group), -N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -S(C0-C 10 alkyl group), -C(O)(C0-C 10 alkyl group), -C(O)O(C0-C 10 alkyl group), -OC(O)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)SO2(C0-C 10 alkyl group), -SO2N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)C(O)(C0-C 10 alkyl group), -C(O)N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -SO2(C0-C 10 alkyl group), wherein the alkyl group is optionally substituted by a group selected from halogen, cyano group, hydroxy group, amino group, C1-C6 alkoxy group, C1-C6 alkylamino group, C3-C6 cycloalkyl group, more specifically, R0 is [ka] Selected from.

[0179] In some embodiments of the invention, L2 is C0-C 10 an alkylene group, wherein one or more H atoms in the alkylene group are optionally independently selected from H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azido group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 10 It is substituted by a group selected from a cycloalkylalkyl group, more specifically, L2 is a C1-C6 alkylene group.

[0180] In some embodiments of the invention, the compound has the following structure: [ka] [ka] [ka] In a particular embodiment (4) of the present invention, in formula I, and particularly in formulas II and III, L1 is -Cy- and the B ring, R0, has the above definition of the present invention.

[0181] In some embodiments of the invention, L1 is -Cy- and R0 is [ka] is.

[0182] In some embodiments of the invention, L1 is -Cy- and R0 is -NR 001 R 002 is.

[0183] In some embodiments of the invention, -Cy- is [ka] Selected from.

[0184] In some embodiments of the invention, L2 is a single bond or C2-C 10 an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from —N(R4)—, —N(R4)C(O)—, —C(O)N(R4)—, —N(R4)S(O)2—, —S(O)2N(R4)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, or —S(O)2, and wherein one or more H atoms in the alkylene group are optionally independently replaced by H, a C1-C6 alkyl group, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an azide group, a hydroxy group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C4-C6 10 More specifically, L2 is a C2-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, and -S-. Specifically, L2 is a single bond, [ka] can be selected from.

[0185] specifically, [ka] The part is [ka] It may have the structure:

[0186] In some embodiments of the present invention, [ka] The part is [ka] More specifically, R1 is a C1-C6 alkyl group, a halogen, a C1-C6 halogenated alkyl group, a cyano group, a nitro group, an azide group, -O(C0-C 10 alkyl group), -S(C0-C 10 alkyl group), -C(O)(C0-C 10 alkyl group), -C(O)O(C0-C 10 alkyl group), -OC(O)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)SO2(C0-C 10 alkyl group), -SO2N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -N(C0-C 10 alkyl group)C(O)(C0-C 10 alkyl group), -C(O)N(C0-C 10 Alkyl group)(C0-C 10 alkyl group), -SO2(C0-C 10 alkyl groups), wherein the alkyl groups are optionally substituted with a group selected from halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl, and more particularly, R1 is selected from halogen (e.g., F, Cl, Br). In a particular embodiment of the invention, [ka] Part [ka] is.

[0187] In some embodiments of the invention, the compound has the following structure: [ka] The technical solutions of the present invention will be described clearly and completely in accordance with the embodiments of the present invention below, but it should be understood that the described embodiments are only a part of the embodiments of the present invention, and are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments that can be obtained by those skilled in the art without any creative efforts fall within the protection scope of the present invention.

[0188] Synthesis Examples: Example 1: Synthesis of Compound T002 The synthetic route is as follows: [ka] Step 1 (1-methyl-1H-indazol-3-yl)methanol (1-methyl-1H-indazol-3-yl)methanol 1-Methyl-1H-indazole-3-carboxylic acid I001 (2.0 g, 11.4 mmol) was dissolved in anhydrous THF (20 mL) and cooled to -78 °C under nitrogen gas protection. DIBAL-H (22.8 mL, 1 M in hexane, 22.8 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for an additional 1 h. The reaction mixture was cooled to 0 °C and quenched with 1 M aqueous HCl (30 mL). The mixture was separated and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (1-methyl-1H-indazol-3-yl)methanol I002 (1.2 g, yellow liquid, 65% yield).

[0189] MS-ESI calculated value [M+H] + 163.1, actual measurement 162.9.

[0190] Step 2 (1-methyl-1H-indazol-3-yl)methyl 4-methylbenzenesulfonate (1-methyl-1H-indazol-3-yl)4-methylbenzenesulfonic acid (1-Methyl-1H-indazol-3-yl)methanol I002 (1.2 g, 7.4 mmol), triethylamine (1.5 g, 14.8 mmol), and DMAP (90 mg, 0.7 mmol) were dissolved in DCM (30 mL) and cooled to 0 °C under N2(g) protection. TsCl (1.6 g, 8.2 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by chromatography (PE:EA = 10:1) to give (1-methyl-1H-indazol-3-yl)4-methylbenzenesulfonic acid I003 (400 mg, white solid, 23% yield).

[0191] Step 3 dimethyl 2-(mercapto(methylthio)methylene)malonate 2-(mercapto(methylthio)methylene)malonate dimethyl Under nitrogen gas protection, DBU (9.2 g, 60.6 mmol) was dissolved in ACN (30 mL). Dimethyl malonate (I004) (4.0 g, 30.3 mmol) was added dropwise in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes. Carbon disulfide (2.3 g, 30.3 mmol) was added dropwise, and the mixture was stirred in an ice-water bath for 1 hour. Dimethyl sulfate (3.8 g, 30.3 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was heated to 25 °C and stirred for 2 hours. After this, crude 2-(mercapto(methylthio)methylene)dimethyl malonate (I005) was obtained and used directly in the next step.

[0192] Step 4 methyl 3-hydroxy-5-(methylthio)isothiazole-4-carboxylate 3-Hydroxy-5-(methylthio)isothiazole-4-carboxylic acid methyl ester Under nitrogen gas protection, sodium bicarbonate (3.0 g, 15.2 mmol) was dissolved in water (30 mL), and hydroxylamine-O-sulfonic acid (4.1 g, 36.4 mmol) was added dropwise in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath. Crude 2-(mercapto(methylthio)methylene)dimethyl malonate I005 was added dropwise, and the reaction mixture was stirred overnight at 25 °C. The mixture was concentrated under reduced pressure to remove acetonitrile, and the pH of the reaction mixture was adjusted to 1 with concentrated hydrochloric acid. The solid was collected by suction filtration. The solid was washed with water (20 mL) and EA / PE (10:1, 20 mL), and dried to give 3-hydroxy-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I006 (4.7 g, yellow solid, two-step yield: 76%).

[0193] MS-ESI calculated value [M+H] + 206.3, actual measurement 205.9.

[0194] 1 H NMR(400 MHz, DMSO-d6) δ = 11.90 (brs, 1H), 3.76 (s, 3H), 2.56 (s, 3H) Step 5 methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I006 (3.7 g, 18.0 mmol) and triethylamine (2.4 g, 23.5 mmol) were dissolved in DCM (30 mL) and cooled to 0 °C under nitrogen gas protection. Ethyl chloroformate (2.3 g, 21.6 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, added anhydrous acetonitrile (40 mL), and concentrated under reduced pressure to remove dichloromethane to give a solution of 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I007 in acetonitrile, which was used directly in the next step.

[0195] Step 6 methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester Under nitrogen gas protection, a solution of 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I007 in acetonitrile was cooled to 0°C, urea peroxide (4.6 g, 50.5 mmol) was added, and trifluoroacetic anhydride (10.6 g, 50.5 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, and then quenched with sodium hydrogen sulfite (3.8 g, 36.1 mmol) and water (40 mL). The mixture was concentrated under reduced pressure to remove acetonitrile, and the aqueous solution was separated and extracted with dichloromethane (30 mL x 2). The organic phase was washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, added with methanol (50 mL), and concentrated under reduced pressure to remove dichloromethane to give a methanol solution of 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I008, which was used directly in the next step.

[0196] Step 7 methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester A solution of 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I008 in methanol was cooled to 0°C, and a solution (40 mL) of 98% concentrated sulfuric acid (20 mL) in water was added dropwise to the reaction mixture. The reaction mixture was stirred at 60°C overnight. The mixture was concentrated under reduced pressure to remove methanol, and the mixture was separated and extracted with dichloromethane (40 mL x 2). The organic phase was washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was slurried in n-hexane (50 mL) to give 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (3.1 g, yellow solid, three-step yield: 74%).

[0197] MS-ESI calculated value [M+H] + 238.0, actual measurement 237.8.

[0198] 1 H NMR (400 MHz, DMSO-d6) δ = 13.07 (brs, 1H), 3.86 (s, 3H), 3.57 (s, 3H).

[0199] Step 8 methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (400 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) were dissolved in DMSO (10 mL), and (1-methyl-1H-indazol-3-yl)4-methylbenzenesulfonic acid I003 (537 mg, 1.7 mmol) was added. The reaction mixture was stirred at 25°C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mL × 2). The organic phase was successively washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by chromatography column (PE:EA = 1:1) to obtain 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I010 (350 mg, white solid, yield: 54%).

[0200] MS-ESI calculated value [M+H] + 382.1, actual measurement 381.9.

[0201] 1 H NMR(400 MHz, DMSO-d6) δ = 7.91 (d, J=10.8 Hz, 1H), 7.49-7.44 (m, 1H), 7.91 (t, J=9.6 Hz, 1H), 5.83 (s, 2H), 4.08 (s,3H), 3.85 (s, 3H), 3.63 (s, 3H). Step 9 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((1-Methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I010 (270 mg, 0.7 mmol) was dissolved in THF (10 mL), 2,4-dimethoxybenzylamine (1.2 g, 7.1 mmol) was added, and the reaction mixture was stirred at 65 °C overnight. The reaction mixture was directly concentrated under reduced pressure to give the crude product, which was purified by chromatography column (PE:EA = 1:1) to give 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I011 (310 mg, yellow solid, yield: 93%).

[0202] MS-ESI calculated value [M+H] + 469.2, actual measurement 469.0.

[0203] 1 H NMR(400 MHz, DMSO-d6) δ = 8.17 (t, J=5.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.44-7.39 (m, 2H), 7.21-7.16 (m, 2H), 6.50-6.46 (m, 2H), 5.80 (s, 2H), 4.31(d, J=6.0 Hz, 2H), 4.10 (s, 3H), 3.88 (s,3H), 3.84 (s, 3H), 3.78 (s, 3H). Step 10 methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I011 (230 mg, 0.5 mmol) was dissolved in DCM / HO (10 / 2 mL), DDQ (446 mg, 2.0 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed sequentially with saturated sodium bicarbonate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography to give the product, 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I012 (150 mg, yellow solid, yield: 96%).

[0204] MS-ESI calculated value [M+H] + 319.1, actual measurement 319.0.

[0205] Step 11 methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (100 mg, 0.7 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen gas protection. CDI (113 mg, 0.7 mmol) was added and the mixture was stirred at 0°C for 40 minutes, then stirred at 25°C for an additional 30 minutes. DMSO (5 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I012 (150 mg, 0.5 mmol) and potassium carbonate (318 mg, 1.0 mmol) were added, and the mixture was stirred at 25°C overnight. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mL × 2). The organic phase was successively washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by chromatography column (DCM:MeOH = 10:1) to obtain 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I013 (170 mg, yellow solid, yield: 70%).

[0206] MS-ESI calculated value [M+H] + 487.2, actual measurement 487.0.

[0207] 1H NMR(400 MHz, DMSO-d6) δ = 10.40 (brs, 1H), 8.32 (t, J=4.2 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.44-7.39 (m, 1H), 7.16 (d, J=7.6 Hz, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 3.74 (s,3H), 3.57-3.40 (m, 2H), 3.19-3.14 (m, 2H), 3.12-3.02 (m, 2H), 2.90-2.87 (m, 2H), 2.06-1.80 (m, 4H), 1.66-1.62 (m, 2H), 1.54-1.47 (m, 2H). Step 12 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I013 (170 mg, 0.35 mmol) was dissolved in anhydrous THF (1 mL), and ammonia-methanol (7N, 4 mL) was added. The mixture was stirred at 50 °C for 96 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography (NaHCO) to give 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T002 (80 mg, white solid, yield: 49%).

[0208] MS-ESI calculated value [M+H] + 472.2, measured value 472.2.

[0209] 1 H NMR(400 MHz, DMSO-d6) δ = 10.99 (s, 1H), 8.18 (t, J=4.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.43 (t, J=8.4 Hz, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.94 (s, 1H), 5.73 (s, 2H), 4.05 (s, 3H), 3.13-3.09 (m, 2H), 2.39-2.31 (m, 6H), 1.67-1.60 (m, 4H), 1.46-1.42 (m, 4H). Example 2: Synthesis of Compound T003 The synthetic route is as follows: [ka] Step 1 methyl 3-(2-bromoethoxy)benzoate Methyl 3-(2-bromoethoxy)benzoate Under nitrogen gas protection, methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol) was dissolved in acetone (150 mL), and 1,2-dibromoethane (74.2 g, 0.39 mol) and potassium carbonate (18.2 g, 0.13 mol) were added. The mixture was stirred at 80 °C overnight. Water (150 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (150 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography (PE:EA = 10:1) to give methyl 3-(2-bromoethoxy)benzoate I014 (6.1 g, colorless liquid, yield: 36%).

[0210] 1H NMR(400 MHz, CDCl3) δ = 7.59 (d, J=7.2 Hz, 1H), 7.49 (dd, J=2.0, 2.8 Hz, 1H), 7.28 (t, J=8.4 Hz, 1H), 7.06-7.04 (m, 1H), 4.26 (t, J=6.0 Hz, 2H), 3.84 (s, 3H), 3.58 (t, J=6.0 Hz, 2H). Step 2 methyl 3-(vinyloxy)benzoate Methyl 3-(vinyloxy)benzoate Under nitrogen gas protection, methyl 3-(2-bromoethoxy)benzoate I014 (3.0 g, 11.6 mmol) was dissolved in anhydrous THF (20 mL), and 1 M potassium tert-butoxide in tetrahydrofuran (23 mL, 23.2 mmol) was added. The mixture was stirred overnight at room temperature. Water (50 mL) was added, and the mixture was separated and extracted with ethyl acetate (50 mL x 2). The organic phase was washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 3-(vinyloxy)benzoate I015 (1.7 g, colorless liquid, 82% yield).

[0211] Step 3 methyl 3-cyclopropoxybenzoate Methyl 3-cyclopropoxybenzoate Under nitrogen gas protection, methyl 3-(vinyloxy)benzoate I015 (1.7 g, 9.6 mmol) was dissolved in anhydrous DCM (20 mL), diiodomethane (10.2 g, 38.2 mmol) was added, the mixture was cooled to 0 °C, diethylzinc (19 mL, 19.1 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. 1N dilute hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was separated and extracted with DCM (20 mL x 2). The combined organic phase was washed sequentially with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give methyl 3-cyclopropoxybenzoate I016 (1.1 g crude, colorless liquid), which was used directly in the next step.

[0212] Step 4 (3-cyclopropoxyphenyl)methanol (3-Cyclopropylphenyl)methanol Methyl 3-cyclopropoxybenzoate I016 (1.1 g, 6.8 mmol) was dissolved in anhydrous THF (10 mL) under nitrogen gas protection. LAH (327 mg, 8.6 mmol) was added under ice-water bath conditions. The mixture was stirred for 30 minutes. The reaction was quenched with water (0.3 mL), followed by 15% sodium hydroxide (0.3 mL) and water (0.9 mL). The mixture was dried over magnesium sulfate, filtered through diatomaceous earth, and the solid was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography (PE:EA = 8:1) to give (3-cyclopropylphenyl)methanol I017 (870 mg, colorless liquid, 92% yield).

[0213] MS-ESI calculated value [M-OH] + 147.2, actual measurement 147.0.

[0214] 1H NMR(400 MHz, CDCl3) δ =7.26-7.24 (m, 1H), 7.06 (d, J=2.0 Hz, 1H), 6.98-6.94 (m, 2H), 4.67 (s, 2H), 3.76-3.71 (m, 1H), 0.81-0.76 (m, 4H). Step 5 3-cyclopropoxybenzyl 4-methylbenzenesulfonate 3-Cyclopropoxybenzyl 4-methylbenzenesulfonate (3-Cyclopropylphenyl)methanol I017 (870 mg, 5.3 mmol), triethylamine (1.1 g, 10.6 mmol), and DMAP (65 mg, 0.5 mmol) were dissolved in DCM (10 mL) and cooled to 0 °C under nitrogen gas protection. TsCl (1.3 g, 6.8 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed sequentially with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by chromatography (PE:EA = 10:1) to give 3-cyclopropoxybenzyl 4-methylbenzenesulfonate I018 (481 mg, colorless liquid, 29% yield).

[0215] Step 6 methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((3-Cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (235 mg, 1.0 mmol) and potassium carbonate (410 mg, 3.0 mmol) were dissolved in DMSO (5 mL). 3-Cyclopropoxybenzyl 4-methylbenzenesulfonate I018 (537 mg, 1.7 mmol) was added, and the reaction mixture was stirred at 25 °C overnight. Water (20 mL) was added, and the mixture was separated and extracted with ethyl acetate (25 mL x 2). The organic phase was washed sequentially with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography (PE:EA = 5:1) to give 3-((3-cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I019 (210 mg, yellow solid, yield: 55%).

[0216] MS-ESI calculated value [M+H] + 384.1, actual measurement 383.8.

[0217] 1 H NMR(400 MHz, CDCl3) δ = 7.31-7.27 (m, 1H), 7.13 (d, J=2.0 Hz, 1H), 7.05-7.01 (m, 2H), 5.46 (s,2H), 3.95 (s,3H), 3.75-3.72 (m, 1H), 3.47 (s, 3H), 0.80-0.76 (m, 4H). Step 7 methyl 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((3-Cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I019 (220 mg, 0.6 mmol) was dissolved in THF (5 mL), and 2,4-dimethoxybenzylamine (478 mg, 2.9 mmol) was added. The reaction mixture was stirred at 60 °C overnight. The reaction mixture was directly concentrated under reduced pressure to give the crude product, which was purified by chromatography column (PE:EA = 5:1) to give 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I020 (182 mg, yellow solid, yield: 68%).

[0218] MS-ESI calculated value [M+H] + 471.1, actual measurement 470.9.

[0219] Step 8 methyl 5-amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I020 (170 mg, 0.4 mmol) was dissolved in DCM / HO (5 / 1 mL), DDQ (327 mg, 1.4 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. DCM (15 mL) was added to the reaction mixture, and the mixture was washed sequentially with saturated aqueous sodium bicarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography (PE:EA=4:1) to give the product, 5-amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I021 (110 mg, yellow solid, yield: 94%).

[0220] MS-ESI calculated value [M+H] + 321.0, actual measurement 320.9.

[0221] Step 9 methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((3-Cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (66 mg, 0.5 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen gas protection. CDI (76 mg, 0.5 mmol) was added and the mixture was stirred at 0°C for 40 minutes, then stirred at 25°C for an additional 30 minutes. DMSO (5 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I021 (100 mg, 0.3 mmol) and potassium carbonate (86 mg, 0.6 mmol) were added, and the reaction mixture was stirred at 25°C overnight. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mL × 2). The organic phase was successively 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 chromatography column (DCM:MeOH = 10:1) to obtain 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I022 (120 mg, white solid, yield: 79%).

[0222] MS-ESI calculated value [M+H] + 489.2, actual measurement 489.0.

[0223] 1H NMR(400 MHz, DMSO-d6) δ = 10.41 (brs, 1H), 8.43 (t, J=4.2 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.15-7.12 (m, 1H), 7.04-6.98 (m, 2H), 5.33 (s, 2H), 3.86-3.77 (m, 4H), 3.19-3.08 (m, 6H), 2.54 (overlap,2H), 1.98-1.86 (m, 4H), 1.71-1.65 (m, 2H), 1.54-1.49 (m, 2H), 0.87-0.80 (m, 2H), 0.66-0.62 (m, 2H). Step 10 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I022 (120 mg, 0.2 mmol) was dissolved in anhydrous THF (2 mL), and ammonia-methanol (7N, 6 mL) was added. The mixture was stirred at 50°C for 96 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography (NaHCO3) to give 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T003 (120 mg, white solid, yield: 59%).

[0224] MS-ESI calculated value [M+H] + 474.2, measured value 474.2.

[0225] 1H NMR(400 MHz, DMSO-d6) δ = 8.16 (s, 1H), 7.62 (s, 1H), 7.31 (t, J=8.0 Hz, 1H), 8.17-8.14 (m, 1H), 7.10-7.00 (m, 3H), 5.38 (s, 2H), 3.83-3.79 (m, 1H), 3.13-3.09 (m, 2H), 2.40-2.32 (m, 6H), 1.67-1.63 (m, 4H), 1.46-1.44 (m, 4H), 0.79-0.75 (m, 2H), 0.65-0.61 (m, 2H). Example 3: Synthesis of Compound T004 The synthetic route is as follows: [ka] Step 1 methyl 1-methyl-1H-indazole-4-carboxylate 1-Methyl-1H-indazole-4-carboxylic acid methyl ester Under nitrogen gas protection, 1H-indazole-4-carboxylic acid methyl ester (2.0 g, 11.4 mmol) was dissolved in DMF (15 mL). 60% sodium hydride (684 mg, 17.1 mmol) was added under ice-water bath conditions. The mixture was stirred for 30 minutes in an ice-water bath. After that, iodomethane (2.4 g, 17.1 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice-water (50 mL). The mixture was separated and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography (PE:EA = 1:1) to give 1-methyl-1H-indazole-4-carboxylic acid methyl ester I023 (1.2 g, white solid, yield: 55%).

[0226] MS-ESI calculated value [M+H] + 472.2, measured value 472.2.

[0227] 1H NMR(400 MHz, DMSO-d6) δ = 8.47 (d, J=0.8 Hz, 1H), 7.92 (dd, J=0.4, 6.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.44 (dd, J=7.2, 7.4 Hz, 1H), 4.11 (s, 3H), 4.01 (s, 3H). Step 2 (1-methyl-1H-indazol-4-yl)methanol (1-methyl-1H-indazol-4-yl)methanol Under nitrogen gas protection, 1-methyl-1H-indazole-4-carboxylic acid methyl ester I023 (1.3 g, 6.8 mmol) was dissolved in anhydrous THF (15 mL). LAH (312 mg, 8.2 mmol) was added under ice-water bath conditions. The mixture was stirred for 30 minutes. The reaction was quenched with water (0.3 mL), followed by 15% sodium hydroxide (0.3 mL) and water (0.9 mL). The mixture was dried over magnesium sulfate, filtered through diatomaceous earth, and the solid was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give (1-methyl-1H-indazol-4-yl)methanol I024 (900 mg, colorless liquid, 82% yield).

[0228] MS-ESI calculated value [M+H] + 163.1, actual measurement 163.0.

[0229] Step 3 (1-methyl-1H-indazol-4-yl)methyl 4-methylbenzenesulfonate (1-methyl-1H-indazol-4-yl)4-methylbenzenesulfonic acid (1-Methyl-1H-indazol-4-yl)methanol I024 (900 mg, 5.6 mmol), triethylamine (1.1 g, 11.2 mmol), and DMAP (68 mg, 0.6 mmol) were dissolved in DCM (15 mL) and cooled to 0 °C under nitrogen gas protection. TsCl (1.3 g, 6.7 mmol) was added and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by chromatography (PE:EA = 10:1) to give (1-methyl-1H-indazol-3-yl)4-methylbenzenesulfonic acid I025 (400 mg, white solid, 32% yield).

[0230] Step 4 methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (400 mg, 1.7 mmol) and potassium carbonate (466 mg, 3.38 mmol) were dissolved in DMSO (10 mL), and (1-methyl-1H-indazol-4-yl)4-methylbenzenesulfonic acid I025 (537 mg, 1.7 mmol) was added. The reaction mixture was stirred at 25°C overnight. Water (30 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (40 mL × 2). The organic phase was successively 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 chromatography column (PE:EA = 1:1) to obtain 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I026 (410 mg, white solid, yield: 63%).

[0231] MS-ESI calculated value [M+H] + 382.1, actual measurement 381.9.

[0232] 1 H NMR (400 MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.44-7.42 (m, 2H), 7.26-7.24 (m, 1H), 4.14 (s, 3H), 3.99 (s,3H), 3.52 (s, 3H).

[0233] Step 5 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((1-Methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I026 (510 mg, 1.3 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (2.2 g, 13.4 mmol) was added. The reaction mixture was stirred at 65 °C overnight. The reaction mixture was directly concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography column (PE:EA = 1:1) to give 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I027 (450 mg, yellow solid, yield: 72%).

[0234] MS-ESI calculated value [M+H] + 469.2, actual measurement 469.0.

[0235] Step 6 methyl 5-amino-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I027 (430 mg, 0.9 mmol) was dissolved in DCM / HO (10 / 2 mL), DDQ (834 mg, 3.7 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography to give the product, 5-amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I028 (240 mg, yellow solid, yield: 84%).

[0236] MS-ESI calculated value [M+H] + 319.1, actual measurement 319.0.

[0237] Step 7 methyl3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (170 mg, 1.2 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (194 mg, 1.2 mmol) was added and the mixture was stirred at 0 °C for 40 minutes, then stirred at 25 °C for an additional 30 minutes. DMSO (5 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I028 (240 mg, 0.8 mmol) and potassium carbonate (221 mg, 1.6 mmol) were added, and the reaction mixture was stirred at 25 °C overnight. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mL × 2). The organic phase was then washed with saturated brine (60 mL). mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by chromatography column (DCM:MeOH=10:1) to give 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I029 (210 mg, yellow solid, yield: 57%).

[0238] MS-ESI calculated value [M+H] + 487.2, actual measurement 487.0.

[0239] 1H NMR(400 MHz, DMSO-d6) δ = 10.41 (brs, 1H), 8.36 (t, J=4.2 Hz, 1H), 8.19 (d, J=0.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.40-7.36 (m, 1H), 7.20 (d, J=6.8 Hz, 1H), 5.67 (s, 2H), 4.05 (s, 3H), 3.81 (s,3H), 3.48-3.40 (m, 2H), 3.19-3.07 (m, 2H), 3.01-2.96 (m, 2H), 2.94-2.85 (m, 2H), 1.92-1.84 (m, 4H), 1.71-1.62 (m, 2H), 1.54-1.47 (m, 2H). Step 8 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I029 (210 mg, 0.4 mmol) was dissolved in anhydrous THF (2 mL), and ammonia-methanol (7N, 6 mL) was added. The mixture was stirred at 50 °C for 96 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography (NaHCO3) to give 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T004 (120 mg, white solid, yield: 59%).

[0240] MS-ESI calculated value [M+H] + 472.2, measured value 472.2.

[0241] 1 H NMR(400 MHz, DMSO-d6) δ = 11.01 (s, 1H), 8.19-8.16 m, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (s, 1H), 7.39 (t, J=7.2 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 7.01 (s, 1H), 5.73 (s, 2H), 4.06 (s, 3H), 3.13-3.09 (m, 2H), 2.39-2.35 (m, 6H), 1.67-1.60 (m, 4H), 1.46-1.42 (m, 4H). Example 4: Synthesis of Compound T005 The synthetic route is as follows: [ka] Step 1 5-bromo-2-(bromomethyl)pyridine 5-Bromo-2-(bromomethyl)pyridine 5-Bromopyridin-2-yl)methanol (2.5 g, 13 mmol) was dissolved in THF (30 mL) and cooled to 0 °C. PBr (10.8 g, 39 mmol) was added and the reaction mixture was stirred at room temperature for approximately 16 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, 5-bromo-2-(bromomethyl)pyridine I030 (4 g, crude product), as a red oily liquid.

[0242] The product was confirmed by LCMS.

[0243] Step 2 methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((5-Bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (2 g, 8.4 mmol) and potassium carbonate (2.3 g, 16.8 mmol) were dissolved in DMSO (30 mL). 5-Bromo-2-(bromomethyl)pyridine I030 (2.3 g, 9.2 mmol) was added and the reaction mixture was stirred at 25 °C for 5 hours. Water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography (PE / EA = 5 / 1 - 2 / 1) to give the white solid product, 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I031 (2 g, 58.8% yield).

[0244] The product was confirmed by LCMS.

[0245] Step 3 methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((5-Bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I031 (2 g, 4.9 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (8.2 g, 49 mmol) was added. The reaction mixture was stirred at 65° C. overnight. The reaction mixture was directly concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography column (PE / EA=10 / 1-5 / 1) to give 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I032 (2.5 g, crude product) as a yellow oil.

[0246] The product was confirmed by LCMS.

[0247] Step 4 methyl 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I032 (2.5 g, 5.1 mmol) was dissolved in DCM / HO (10 / 2 mL), DDQ (4.6 g, 20.4 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography column (PE / EA = 5 / 1-3 / 1) to give the yellow solid product, 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I033 (1.3 g, 74.7% yield).

[0248] The product was confirmed by LCMS.

[0249] Step 5 methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (170 mg, 1.2 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen gas protection. CDI (194 mg, 1.2 mmol) was added and the mixture was stirred at 0°C for 40 minutes, then stirred at 25°C for an additional 30 minutes. DMSO (5 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I033 (1.3 g, 3.8 mmol) and potassium carbonate (1.1 g, 7.6 mmol) were added, and the mixture was stirred at 25°C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mLx3). The organic phase was 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 chromatography column (PE / EA=1 / 1-1 / 2) to obtain the colorless liquid product 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I034 (700 mg, 36.6% yield).

[0250] The product was confirmed by LCMS.

[0251] Step 6 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I034 (300 mg, 0.59 mmol) was dissolved in NH3 / MeOH (4 mL, 13 mol / L), and the mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography to give the white solid product, 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T005 (29 mg, 10% yield).

[0252] The product was confirmed by LCMS, H-NMR and C-NMR.

[0253] 1 H NMR (400 MHz, CD3OD) δ: 8.68 (d, 1H, J=2.0Hz), 8.04 (dd, 1H, J=8.0, 2.0Hz), 7.48 (d, 1H, J=8.0Hz), 5.55 (s, 2H), 3.28 (t, 2H, J=6.0Hz), 2.57-2.65 (m, 6H), 1.84-1.87 (m, 4H), 1.61-1.63 (m, 4H). 13 C NMR (100 MHz, CD3OD) δ: 169.02, 165.79, 154.81, 154.75, 149.92, 139.82, 123.61, 119.67, 69.14, 55.76, 53.57, 39.53, 27.47, 25.49, 22.74. Example 5: Synthesis of Compound T006 The synthetic route is as follows: [ka] Step 1 methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((3,5-Dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMSO (10 mL), and 1-(bromomethyl)-3,5-dimethoxybenzene I035 (1.06 g, 4.64 mmol) was added. The reaction mixture was stirred at 25°C for 16 hours. Water (30 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mLx3). The organic phase was washed successively with water (50 mL) and 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 chromatography column (PE / EA = 10 / 1 to 2 / 1) to obtain the yellow solid product 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I036 (0.5 g, 30.6% yield).

[0254] The product was confirmed by LCMS and H-NMR.

[0255] 1 H NMR (400 MHz, CDCl3) δ: 6.63 (d, 2H, J=2.0Hz), 6.45 (t, 1H, J=2.4Hz), 5.45 (s, 2H), 3.99 (s, 3H), 3.89 (s, 6H), 3.50 (s, 3H). Step 2 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((3,5-Dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I036 (0.5 g, 1.29 mmol) was dissolved in THF (5 mL), and 2,4-dimethoxybenzylamine (2.16 g, 12.9 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. 1N HCl solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid crude product, 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I037 (0.6 g, 98.0% yield).

[0256] The product was confirmed by LCMS and H-NMR.

[0257] 1 H NMR (400 MHz, CDCl3) δ: 8.16 (t, 1H, J=6.0Hz), 7.18 (d, 1H, J=8.0Hz), 6.65 (d, 2H, J=2.0Hz), 6.45-6.50 (m, 2H), 6.41 (t, 1H, J=2.0Hz), 5.39 (s, 2H), 4.29 (d, 1H, J=6.0Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.82-3.83 (m, 9H). Step 3 methyl 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I037 (0.6 g, 1.26 mmol) was dissolved in DCM / HO (6 / 0.6 mL), and DDQ (0.57 g, 2.53 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL x 3). The combined organic phases were washed successively with water (10 mL x 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography column (PE / EA = 10 / 1 to 2 / 1) to give the yellow solid product, 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I038 (0.35 g, 85.3% yield).

[0258] The product was confirmed by LCMS and H-NMR.

[0259] 1 H NMR (400 MHz, CDCl3) δ: 6.66 (d, 2H, J=2.0Hz), 6.46 (s, 2H), 6.43 (t, 1H, J=2.4Hz), 5.41 (s, 2H), 3.89 (s, 3H), 3.83 (s, 6H). Step 4 methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((3,5-Dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (230 mg, 1.62 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen gas protection. CDI (262 mg, 1.62 mmol) was added and the mixture was stirred at room temperature for 30 minutes. DMSO (5 mL) was added and the THF was removed under reduced pressure. 5-Amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I038 (350 mg, 1.08 mmol) and potassium carbonate (298 mg, 2.16 mmol) were added and the mixture was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (10 mL × 3). The organic phase was washed successively with water (10 mL) and 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 chromatography column (DCM / MeOH = 50 / 1 to 10 / 1) to obtain the colorless liquid product 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I039 (300 mg, 56.4% yield).

[0260] The product was confirmed by LCMS and H-NMR.

[0261] 1 H NMR (400 MHz, CDCl3) δ: 10.43 (s, 1H), 6.67 (d, 2H, J=2.0Hz), 6.41 (t, 1H, J=2.0Hz), 5.41 (s, 2H), 3.91 (s, 3H), 3.82 (s, 6H), 3.39 (t, 2H, J=2.0Hz), 3.08 (s, 3H), 2.94 (t, 2H, J=7.2Hz), 2.06-2.11 (m, 5H), 1.89-1.93 (m, 2H), 1.69-1.72 (m, 2H). Step 5 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3,5-Dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I039 (300 mg, 0.61 mmol) was dissolved in THF (3 mL) and NH3 / MeOH (3 mL, 13 mol / L) in a microwave tube, and the mixture was stirred at 60 °C for 48 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography (DCM / MeOH = 10 / 1, 0.1% NH3.HO) to give the white solid product, 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T006 (50 mg, 17.2% yield).

[0262] The product was confirmed by LCMS, H-NMR and C-NMR.

[0263] 1 H NMR (400 MHz, CDCl3) δ: 10.97 (br s, 1H), 7.80 (br s, 1H), 7.20 (s, 1H), 6.59 (d, 2H, J=2.0Hz), 6.46 (t, 1H, J=2.4Hz), 5.87 (br s, 1H), 5.40 (s, 2H), 3.81 (s, 6H), 3.32-3.34 (m, 2H), 2.63-2.73 (m, 6H), 1.91 (s, 4H), 1.68-1.74 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 169.53, 165.84, 161.86, 161.05, 154.18, 138.19, 106.18, 100.26, 70.37, 55.65, 55.41, 53.88, 27.74, 25.83, 23.39. Example 6: Synthesis of Compound T007 The synthetic route is as follows: [ka] Step 1 5-(bromomethyl)benzo[d][1,3]dioxole 5-(Bromomethyl)benzo[d][1,3]dioxole (2H-1,3-Benzodioxol-5-yl)methanol (2.0 g, 13.2 mmol) was dissolved in DCM (20 mL) and cooled to -40 °C. PBr (3.56 g, 13.2 mmol) was added and the reaction mixture was stirred at -40 °C for approximately 20 minutes. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude white solid product, 5-(bromomethyl)benzo[d][1,3]dioxole I040 (2 g, 70.8% yield).

[0264] The product was confirmed by LCMS and H-NMR.

[0265] 1 H NMR (400 MHz, CDCl3) δ: 6.88-6.90 (m, 2H), 6.78 (d, 1H, J=7.6Hz), 5.99 (s, 2H), 4.48 (s, 2H). Step 2 methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.1 g, 4.64 mmol) and potassium carbonate (1.28 g, 9.27 mmol) were dissolved in DMSO (10 mL), and 5-(bromomethyl)benzo[d][1,3]dioxole I040 (1.0 g, 4.64 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (30 mLx3). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was stirred in MTBE (20 mL) for 20 minutes, filtered, and the filter cake was dried to obtain the yellow solid product, 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I041 (0.85 g, 49.4% yield).

[0266] The product was confirmed by LCMS and H-NMR.

[0267] 1 H NMR (400 MHz, CDCl3) δ: 6.92-6.95 (m, 2H), 6.80 (d, 1H, J=8.0Hz), 5.97 (s, 2H), 5.38 (s, 2H), 3.94 (s, 3H), 3.47 (s, 3H). Step 3 methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I041 (0.85 g, 2.29 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (3.83 g, 22.9 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed sequentially with 1N HCl (10 mL x 2) and saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give crude yellow solid 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I042 (1 g, 95.3% yield).

[0268] The product was confirmed by LCMS and H-NMR.

[0269] 1 H NMR (400 MHz, CDCl3) δ: 8.14 (t, 1H, J=5.6Hz), 7.18 (d, 1H, J=8.0Hz), 7.00 (s, 1H), 6.92-6.94 (m, 1H), 6.81 (d, 1H, J=8.0Hz), 6.45-6.50 (m, 2H), 5.97 (s, 2H), 5.34 (s, 2H), 4.29 (d, 1H, J=6.0Hz), 3.87 (s, 3H), 3.82-3.83 (m, 6H). Step 4 methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate 5-Amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I042 (1.0 g, 2.18 mmol) was dissolved in DCM / HO (10 / 1 mL), and DDQ (0.99 g, 4.36 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Water (10 mL) was added to the reaction mixture, which was then extracted with DCM (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 the crude product, which was purified by chromatography column (PE / EA = 10 / 1 to 2 / 1) to give the yellow solid product, 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester I043 (0.4 g, 59.5% yield).

[0270] The product was confirmed by LCMS and H-NMR.

[0271] 1 H NMR (400 MHz, DMSO-d6) δ: 7.89 (s, 1H), 7.00 (s, 1H), 6.92-6.93 (m, 2H), 6.02 (s, 2H), 5.22 (s, 2H), 3.70 (s, 3H). Step 5 methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido) isothiazole-4-carboxylate 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (277 mg, 1.95 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under nitrogen gas protection. CDI (316 mg, 1.95 mmol) was added and the mixture was stirred at room temperature for 30 minutes. DMSO (5 mL) was added and the THF was removed under reduced pressure. 5-Amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester I043 (400 mg, 1.30 mmol) and potassium carbonate (359 mg, 2.59 mmol) were added and the mixture was stirred at 25°C for 16 hours. Water (15 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (10 mLx3). The organic phase was washed successively with water (10 mL) and 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 chromatography column (DCM / MeOH=10 / 1) to obtain the yellow liquid product, 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I044 (500 mg, 80.9% yield).

[0272] The product was confirmed by LCMS and H-NMR.

[0273] 1 H NMR (400 MHz, CDCl3) δ: 10.27 (br s, 1H), 8.10 (br s, 1H), 7.00 (s, 1H), 6.94 (d, 2H, J=7.6Hz), 6.81 (d, 1H, J=8.0Hz), 5.98 (s, 2H), 5.35 (s, 2H), 3.88 (s, 3H), 3.34(s, 2H), 2.75 (s, 4H), 2.65 (t, 2H, J=6.0Hz), 1.95 (s, 4H), 1.70-1.75 (m, 4H). Step 6 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I044 (200 mg, 0.42 mmol) was dissolved in NH3 / MeOH (4 mL, 13 mol / L), and the mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography to give the white solid product, 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T007 (40 mg, 20.6% yield).

[0274] The product was confirmed by LCMS, H-NMR and C-NMR.

[0275] 1 H NMR (400 MHz, DMSO-d6) δ: 11.01 (s, 1H), 8.20 (s, 1H), 7.61 (s, 1H), 7.11 (d, 1H, J=1.2Hz), 6.98-7.02 (m, 2H), 6.92 (d, 1H, J=8.0Hz), 6.03 (s, 2H), 5.29 (s, 2H), 3.11-3.13 (m, 2H), 2.38-2.41 (m, 6H), 1.66-1.67 (m, 4H), 1.46 (s, 4H). 13C NMR (100 MHz, DMSO-d6) δ: 168.44, 164.93, 162.04, 154.49, 147.81, 147.75, 130.47, 122.97, 109.55, 108.60, 101.57, 97.94, 69.92, 55.66, 54.03, 27.66, 26.11, 23.54. Example 7: Synthesis of Compound T009 The synthetic route is as follows: [ka] Step 1 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole 3-(Bromomethyl)-1,5-dimethyl-1H-pyrazole (1,5-Dimethyl-1H-pyrazol-3-yl)methanol (2.0 g, 15.9 mmol) was dissolved in DCM (40 mL) and cooled to 10 °C. PBr (6.4 g, 23.8 mmol) was added, and the reaction mixture was stirred at room temperature for approximately 16 hours. The reaction mixture was poured into water (50 mL), adjusted to pH 8–9 with solid potassium carbonate, 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 off-white solid product, 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole I049 (2.7 g, 90.1% yield).

[0276] The product was confirmed by LCMS and H-NMR.

[0277] 1 H NMR (400 MHz, CDCl3) δ: 6.09 (s, 1H), 4.46 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H). Step 2 methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.5 g, 6.32 mmol) and potassium carbonate (1.75 g, 12.6 mmol) were dissolved in DMF (15 mL), and 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole I049 (1.26 g, 6.64 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (50 mL) and 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 (DCM / MeOH=20 / 1-10 / 1) to obtain the yellow solid product, 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I050 (0.6 g, 67.4% yield).

[0278] The product was confirmed by LCMS and H-NMR.

[0279] 1 H NMR (400 MHz, CDCl3) δ: 6.16 (s, 1H), 5.44 (s, 2H), 3.94 (s, 3H), 3.79 (s, 3H), 3.48 (s, 3H), 2.29 (s, 3H). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((1,5-Dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I050 (1.9 g, 5.4 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (8.2 g, 49 mmol) was added. The reaction mixture was stirred at 65°C for 3 hours. After completion of the reaction, the reaction mixture was added to water (100 mL), adjusted to pH 4 with 4N HCl solution, and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under pressure to obtain a yellow solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I051 (2.5 g, 99.6% yield).

[0280] The product was confirmed by LCMS and H-NMR.

[0281] 1 H NMR (400 MHz, CDCl3) δ: 8.12 (t, 1H, J=5.6Hz), 7.18 (d, 1H, J=8.0Hz), 6.44-6.49 (m, 2H), 6.15 (s, 1H), 5.37 (s, 2H), 4.28 (d, 1H, J=6.0Hz), 3.86 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.77 (s, 3H), 2.27 (s, 3H). Step 4 methyl 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I051 (1.5 g, 3.45 mmol) was dissolved in DCM / HO (15 / 3 mL), and DDQ (0.94 g, 4.14 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 10 minutes. Water (20 mL) was added to the reaction mixture, which was then extracted with DCM (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by chromatography column (neutral aluminum oxide, PE / EA = 5 / 1-3 / 1-1 / 1-1 / 2) to give the yellow solid product, 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I052 (0.78 g, 80% yield).

[0282] The product was confirmed by LCMS and H-NMR.

[0283] 1 H NMR (400 MHz, CDCl3) δ: 6.54 (s, 2H), 6.16 (s, 1H), 5.38 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 2.27 (s, 3H). Step 5 methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (281 mg, 1.97 mmol) was dissolved in anhydrous THF (25 mL) and cooled to 0 °C under nitrogen gas protection. CDI (448 mg, 2.76 mmol) was added and the mixture was stirred at room temperature for 60 minutes. DMSO (25 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I052 (780 mg, 2.76 mmol) and potassium carbonate (546 mg, 3.95 mmol) were added, and the reaction mixture was stirred at 25 °C for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mL x 3). The organic phase was then successively washed with water (100 mL), saturated brine (100 mL), and HCl. mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1, 1% NH3.HO) to give the yellow solid product 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I053 (700 mg, 56.2% yield).

[0284] The product was confirmed by LCMS and H-NMR.

[0285] 1 H NMR (400 MHz, CDCl3) δ: 10.27 (br s, 1H), 8.15 (br s, 1H), 6.15 (s, 1H), 5.37 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.32 (t, 2H, J=5.6Hz), 2.66 (s, 4H), 2.58 (t, 2H, J=6.0Hz), 2.26 (s, 3H), 1.89 (s, 4H), 1.68-1.69 (m, 4H). Step 6 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I053 (250 mg, 0.55 mmol) was dissolved in NH3 / MeOH (10 mL, 9.5 mol / L) in a microwave tube, and the mixture was stirred at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.HO) to give the white solid product, 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T009 (75 mg, 31% yield).

[0286] The product was confirmed by LCMS, H-NMR and C-NMR.

[0287] 1 H NMR (400 MHz, CDCl3) δ: 10.91 (br s, 1H), 7.74 (br s, 1H), 6.13 (s, 1H), 5.67 (s, 1H), 5.41 (s, 2H), 3.78 (s, 3H), 3.32 (d, 2H, J=3.6Hz), 2.50-2.57 (m, 6H), 2.28 (s, 3H), 1.85 (s, 4H), 1.66 (d, 4H, J=2.0Hz). 13C NMR (100 MHz, CDCl3) δ: 169.42, 165.96, 161.88, 154.05, 146.03, 139.62, 105.43, 97.44, 64.10, 55.87, 53.93, 40.55, 40.53, 36.10, 28.15, 26.66, 23.41, 11.21. Example 8: Synthesis of Compound T013 The synthetic route is as follows: [ka] Step 1 2-(bromomethyl)imidazo[1,2-a]pyridine 2-(Bromomethyl)imidazo[1,2-a]pyridine {Imidazo[1,2-a]pyridin-2-yl}methanol (1.0 g, 6.7 mmol) was dissolved in DCM (40 mL) and cooled to 0 °C. PBr (3.6 g, 13.4 mmol) was added and the reaction mixture was stirred at room temperature for approximately 12 hours. After the reaction was complete, the mixture was directly concentrated under reduced pressure to give the crude white product, 2-(bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude).

[0288] The product was confirmed by LCMS.

[0289] Step 2 methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-(Imidazo[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.9 g, 3.8 mmol) and potassium carbonate (1.0 g, 7.6 mmol) were dissolved in DMF (20 mL). 2-(Bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude product) was added and the reaction mixture was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude yellow solid product, 3-(imidazo[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I072 (0.9 g, 66.7% yield).

[0290] The product was confirmed by LCMS and H-NMR.

[0291] 1 H NMR (400 MHz, CDCl3) δ: 8.12 (d, 1H, J=6.8Hz), 7.71 (s, 1H), 7.62 (d, 1H, J=9.2Hz), 7.21-7.23 (m, 1H), 6.82-6.85 (m, 1H), 5.70 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylic acid methyl ester 3-(Imidazo[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I072 (0.9 g, 2.4 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (4.0 g, 24 mmol) was added. The reaction mixture was stirred at 65 °C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, and cold water (40 mL) was added. The solid was filtered, washed with water (10 mL x 3), and dried to give the white solid product, 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylic acid methyl ester I073 (0.9 g, 81.9% yield).

[0292] The product was confirmed by LCMS and H-NMR.

[0293] 1 H NMR (400 MHz, CDCl3) δ: 8.09-8.10 (m, 2H), 7.68 (s, 1H), 7.60 (d, 1H, J=9.2Hz), 7.17-7.19 (m, 2H), 6.78-6.79 (m, 1H), 6.44-6.49 (m, 2H), 5.63 (s, 2H), 4.29 (d, 2H, J=5.6Hz), 3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H). Step 4 methyl 5-amino-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate 5-Amino-3-(imidazo[1,2-a]pyridine-2-methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylic acid methyl ester I073 (0.9 g, 2.0 mmol) was dissolved in DCM / HO (25 / 5 mL), and DDQ (1.8 g, 8.0 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to the reaction mixture, which was washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the white solid product, 5-amino-3-(imidazo[1,2-a]pyridine-2-methoxy)isothiazole-4-carboxylic acid methyl ester I074 (250 mg, 37.3% yield).

[0294] The product was confirmed by LCMS and H-NMR.

[0295] 1 H NMR (400 MHz, CDCl3) δ: 8.11 (d, 1H, J=6.8Hz), 7.70 (s, 1H), 7.61 (d, 1H, J=8.8Hz), 7.17-7.21 (m, 1H), 6.80 (t, 1H, J=6.8Hz), 6.59 (s, 1H), 5.64 (s, 2H), 3.87 (s, 3H). Step 5 methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (125 mg, 0.88 mmol) was dissolved in anhydrous THF (6 mL) and cooled to 0 °C under nitrogen gas protection. CDI (143 mg, 0.88 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (6 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-(imidazo[1,2-a]pyridine-2-methoxy)isothiazole-4-carboxylic acid methyl ester I074 (200 mg, 0.64 mmol) and potassium carbonate (177 mg, 1.28 mmol) were added and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, water (40 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL×3). The organic phase was washed successively with water (30 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1, 1% NH3.HO) to obtain the white solid product 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I075 (130 mg, 43% yield).

[0296] The product was confirmed by LCMS and H-NMR.

[0297] 1 H NMR (400 MHz, CDCl3) δ: 10.10 (br s, 1H), 8.20 (br s, 1H), 8.11 (d, 1H, J=6.8Hz), 7.71 (s, 1H), 7.58-7.60 (m, 1H), 7.18 (t, 1H, J=7.2Hz), 6.79 (t, 1H, J=6.8Hz), 5.64 (s, 2H), 3.82 (s, 3H), 3.34 (s, 2H), 2.63-2.73 (m, 6H), 1.94 (s, 4H), 1.71-1.75 (m, 4H). Step 6 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I075 (140 mg, 0.28 mmol) was dissolved in anhydrous THF (2.5 mL) and NH3 / MeOH (10 mL, 8 mol / L), and the mixture was sealed at 60 °C and reacted for 60 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O=10 / 1 / 0.1) to give the white solid product 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T013 (25 mg, 17.1% yield).

[0298] The product was confirmed by LCMS, H-NMR and C-NMR.

[0299] 1 H NMR (400 MHz, CD3OD) δ: 8.43 (d, 1H, J=6.8Hz), 7.98 (s, 1H), 7.54-7.57 (m, 1H), 7.34-7.38 (m, 1H), 6.95 (t, 1H, J=6.8Hz), 5.60 (s, 2H), 3.27 (t, 2H, J=6.4Hz), 2.78 (s, 4H), 2.68-2.72 (m, 2H), 1.88-1.90 (m, 4H), 1.60-1.67 (m, 4H). 13C NMR (100 MHz, CD3OD) δ: 168. 81, 165.81, 161.82, 154.80, 145.26, 140.40, 126.74, 126.12, 115.97, 112.79, 112.53, 63.44, 55.11, 53.62, 27.02, 24.21, 22.67. Example 9: Synthesis of Compound T015 The synthetic route is as follows: [ka] Step 1 (5-bromothiazol-2-yl)methyl 4-methylbenzenesulfonate (5-Bromothiazol-2-yl)-4-methylbenzenesulfonic acid (5-Bromo-1,3-thiazol-2-yl)methanol (1.0 g, 5.15 mmol) and TsO (1.68 g, 5.15 mmol) were dissolved in DCM (10 mL) and cooled to 0 °C under nitrogen gas protection. Triethylamine (1.04 g, 10.3 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 2). The combined organic phase was washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (PE / EA = 20 / 1 to 2 / 1) to give the yellow solid product (5-bromothiazol-2-yl)-4-methylbenzenesulfonic acid I081 (1.1 g, 61.5% yield).

[0300] The product was confirmed by LCMS and H-NMR.

[0301] 1H NMR (400 MHz, CDCl3) δ: 7.84 (d, 2H, J=8.4Hz), 7.64 (s, 1H), 7.38 (d, 1H, J=8.0Hz), 5.27 (s, 2H), 2.48 (s, 3H). Step 2 methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((5-Bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.8 g, 3.37 mmol) and potassium carbonate (0.93 g, 6.74 mmol) were dissolved in DMSO (10 mL). (5-Bromothiazol-2-yl)-4-methylbenzenesulfonic acid I081 (1.1 g, 3.37 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude yellow solid product, 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I082 (1.3 g, 93.3% yield).

[0302] The product was confirmed by LCMS and H-NMR.

[0303] 1 H NMR (400 MHz, CDCl3) δ: 7.71 (s, 1H), 5.70 (s, 2H), 4.00 (s, 3H), 3.52 (s, 3H). Step 3 methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((5-Bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I082 (1.3 g, 3.15 mmol) was dissolved in THF (13 mL), and 2,4-dimethoxybenzylamine (5.26 g, 31.5 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed sequentially with 1N HCl solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the yellow solid product, 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I083 (1.5 g, 95.3% yield).

[0304] The product was confirmed by LCMS and H-NMR.

[0305] 1 H NMR (400 MHz, CDCl3) δ: 8.17 (s, 1H), 7.67 (s, 1H), 7.18 (d, 1H, J=8.0Hz), 6.45-6.50 (m, 2H), 5.62 (s, 2H), 4.30 (d, 1H, J=6.0Hz), 3.83-3.87 (m, 9H). Step 4 methyl 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I083 (1.5 g, 3.00 mmol) was dissolved in DCM / HO (15 / 3 mL), and DDQ (2.72 g, 12.0 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 40 minutes. After the reaction was completed, water (20 mL) was added to the reaction mixture and extracted with dichloromethane (10 mLx3). The organic phase was 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 (PE / EA = 10 / 1 to 5 / 1) to obtain the yellow solid product 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I084 (0.53 g, 47.6% yield).

[0306] The product was confirmed by LCMS and H-NMR.

[0307] 1 H NMR (400 MHz, DMSO-d6) δ: 7.99 (s, 2H), 7.89 (s, 1H), 5.56 (s, 2H), 3.73 (s, 3H). Step 5 methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (245 mg, 1.72 mmol) was dissolved in anhydrous THF (20 mL) and cooled to 0 °C under nitrogen gas protection. CDI (279 mg, 1.72 mmol) was added and the mixture was stirred at room temperature for 30 minutes. DMSO (20 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I084 (430 mg, 1.23 mmol) and potassium carbonate (339 mg, 2.46 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phase was washed successively with water (40 mL) and 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 (DCM / MeOH=30 / 1 to 20 / 1) to obtain the yellow solid product 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I085 (650 mg, 82.8% yield).

[0308] The product was confirmed by LCMS and H-NMR.

[0309] 1 H NMR (400 MHz, CDCl3) δ: 10.25 (br s, 1H), 8.34 (br s, 1H), 7.68 (s, 1H), 5.64 (s, 2H), 3.91 (s, 3H), 3.35(t, 2H, J=5.2Hz), 2.75 (s, 4H), 2.66 (t, 2H, J=5.2Hz), 1.96 (s, 4H), 1.73-1.77 (m, 4H). Step 6 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester In a microwave tube, 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I085 (400 mg, 0.77 mmol) was dissolved in NH3 / MeOH (3 mL, 10 mol / L), and the mixture was reacted at 60 °C for 16 hours under sealed conditions. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester T015 (50 mg, 12.9% yield).

[0310] The product was confirmed by LCMS, H-NMR and C-NMR.

[0311] 1 H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.23 ​​(t, 1H, J=5.6Hz), 7.92 (s, 1H), 7.68 (s, 1H), 6.14 (s, 1H), 5.66 (s, 2H), 3.13 (d, 2H, J=5.6Hz), 2.47 (s, 6H), 1.68 (s, 4H), 1.47 (s, 4H). 13 C NMR (100 MHz, DMSO-d6) δ: 168.89, 167.19, 164.65, 161.07, 154.54, 144.23, 110.58, 97.80, 66.46, 55.57, 54.00, 27.61, 25.92, 23.52. Example 10: Synthesis of Compound T017 The synthetic route is as follows: [ka] Step 1 4-cyano-2-fluorobenzyl 4-methylbenzenesulfonate 4-Cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid 3-Fluoro-4-(hydroxymethyl)benzonitrile I088 (2.0 g, 13.2 mmol) and TsO (4.32 g, 8.43 mmol) were dissolved in DCM (20 mL) and cooled to 0 °C under nitrogen gas protection. Triethylamine (2.68 g, 26.5 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was extracted with water (40 mL) and dichloromethane. The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 10 / 1 to 2 / 1) to give 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (2.1 g, 52.0% yield) as a white solid.

[0312] The product was confirmed by LCMS and H-NMR.

[0313] 1 H NMR (400 MHz, CDCl3) δ: 7.83 (d, 2H, J=8.4Hz), 7.46-7.54 (m, 2H), 7.34-7.39 (m, 3H), 5.17 (s, 2H), 2.49 (s, 3H). Step 2 methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMSO (10 mL), and 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (1.42 g, 4.64 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by flash column chromatography (PE / EA=10 / 1 to 2 / 1) to obtain the yellow solid product 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I090 (1.4 g, 89.7% yield).

[0314] The product was confirmed by LCMS and H-NMR.

[0315] 1 H NMR (400 MHz, CDCl3) δ: 7.70 (t, 1H, J=8.0Hz), 7.53 (d, 1H, J=7.6Hz), 7.43 (dd, 1H, J=9.6, 1.6Hz), 5.62 (s, 2H), 4.00 (s, 3H), 3.51 (s, 3H). Step 3 methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((4-Cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I090 (1.4 g, 3.78 mmol) was dissolved in THF (15 mL), and 2,4-dimethoxybenzylamine (6.32 g, 37.8 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the yellow solid product, 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I091 (1.7 g, 98.3% yield).

[0316] The product was confirmed by LCMS and H-NMR.

[0317] 1 H NMR (400 MHz, DMSO-d6) δ: 8.45 (t, 1H, J=6.0Hz), 7.90 (d, 1H, J=10.0Hz), 7.70-7.77 (m, 2H), 7.17 (d, 1H, J=8.4Hz), 6.60 (d, 1H, J=4.4Hz), 6.51 (dd, 1H, J=8.4, 2.4Hz), 5.46 (s, 2H), 4.29 (d, 1H, J=6.0Hz), 3.83 (s, 3H), 3.76 (s, 6H). Step 4 methyl 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((4-Cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I091 (1.3 g, 2.84 mmol) was dissolved in DCM / HO (10 / 2 mL), and DDQ (2.58 g, 11.4 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and extracted with dichloromethane (10 mL×3). The organic phase was washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was stirred, dissolved in PE / EA (v / v=3 / 1, 5 mL), and filtered to leave a filter cake, which was washed with dichloromethane (2 mL) and then dried to obtain the yellow solid product, 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I092 (0.6 g, 68.7% yield).

[0318] The product was confirmed by LCMS and H-NMR.

[0319] 1 H NMR (400 MHz, DMSO-d6) δ: 7.89-7.95 (m, 3H), 7.72-7.79 (m, 2H), 5.46 (s, 2H), 3.73 (s, 3H). Step 5 methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (417 mg, 2.93 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (475 mg, 2.93 mmol) was added and the mixture was stirred at room temperature for 30 minutes. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I092 (600 mg, 1.95 mmol) and potassium carbonate (538 mg, 3.90 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phase was washed successively with water (20 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the colorless oily liquid product 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I093 (350 mg, 37.7% yield).

[0320] The product was confirmed by LCMS and H-NMR.

[0321] 1 H NMR (400 MHz, CDCl3) δ: 10.20 (br s, 1H), 8.32 (br s, 1H), 7.74 (t, 1H, J=7.6Hz), 7.50 (d, 1H, J=8.0Hz), 7.37-7.40 (m, 1H), 5.56 (s, 2H), 3.90 (s, 3H), 3.32-3.33 (m, 2H), 2.53-2.59 (m, 4H), 1.90 (s, 4H), 1.78-1.81 (m, 2H), 1.69 (s, 4H). Step 6 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I093 (350 mg, 0.74 mmol) was dissolved in NH3 / MeOH (4 mL, 10 mol / L), and the mixture was reacted with stirring at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give a white solid product, which was stirred and dissolved in acetonitrile (5 mL). The remaining solid product was filtered and dried to give 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T017 (26 mg, 7.7% yield).

[0322] The product was confirmed by LCMS, H-NMR and C-NMR.

[0323] 1 H NMR (400 MHz, CD3OD) δ: 7.71 (d, 1H, J=7.6Hz), 7.59-7.65 (m, 2H), 5.64 (s, 2H), 3.26 (t, 2H, J=6.4Hz), 2.66 (s, 4H), 2.59 (t, 2H, J=7.6Hz), 1.84-1.87 (m, 4H), 1.58-1.64 (m, 4H). 13C NMR (100 MHz, CD3OD) δ: 169.12, 165.68, 161.56, 161.24, 159.08, 154.71, 131.18, 131.13, 129.66, 129.52, 128.30, 128.26, 119.07, 118.82, 116.93, 116.90, 113.49, 113.40, 97.28, 63.11, 63.07, 55.65, 53.59, 39.47, 27.40, 25.29, 22.74. Example 11: Synthesis of Compound T022 The synthetic route is as follows: [ka] Step 1 methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester 5-Hydroxy-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (10 g, 64 mmol) was dissolved in acetonitrile (50 mL), POBr3 (55 g, 192 mmol) was added, and the mixture was heated to 80 °C and stirred for 24 h. After the reaction was complete, the mixture was poured into water (200 mL), adjusted to pH 8 with sodium bicarbonate, extracted with ethyl acetate, and the combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA = 10 / 1) to give the white solid product, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester I099 (5 g, 35.7% yield).

[0324] The product was confirmed by LCMS.

[0325] Step 2 (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol (5-Bromo-1-methyl-1H-pyrazol-3-yl)methanol Under nitrogen gas protection, 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester I099 (2.5 g, 11.4 mmol) was dissolved in dry THF (30 mL). LiBH4 (14 mL, 28.5 mmol, 2 mol / L) was added at 0 °C, and the mixture was heated to room temperature and reacted for approximately 12 hours. After the reaction was complete, the reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 2 / 1) to give (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol I100 (1.5 g, 68.2% yield) as a colorless oil.

[0326] The product was confirmed by LCMS.

[0327] Step 3 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole 5-Bromo-3-(bromomethyl)-1-methyl-1H-pyrazole (5-Bromo-1-methyl-1H-pyrazol-3-yl)methanol I100 (1.5 g, 7.89 mmol) was dissolved in dichloromethane (30 mL) and cooled to 0 °C. PBr3 (3.2 g, 11.9 mmol) was added, and the mixture was heated to room temperature and reacted for 16 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed sequentially with saturated sodium bicarbonate (50 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole I101 (1.65 g, crude product), as a colorless oil.

[0328] The product was confirmed by LCMS.

[0329] Step 4 methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((5-Bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.5 g, 6.33 mmol) was dissolved in anhydrous DMF (20 mL), and K2CO3 (1.75 g, 12.7 mmol) and 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole I101 (1.61 g, 6.33 mmol) were added sequentially at room temperature. The mixture was stirred for approximately 3 hours. After the reaction was completed, the reaction mixture was added to water (80 mL) and extracted with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain the white solid product 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I102 (1.35 g, 51.9% yield).

[0330] The product was confirmed by LCMS and H-NMR.

[0331] 1 H NMR (400 MHz, DMSO-d6) δ: 6.56 (s, 1H), 5.37 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.61 (s, 3H). Step 5 methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((5-Bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I102 (1.5 g, 3.66 mmol) was dissolved in dry THF (20 mL), and 2,4-dimethoxybenzylamine (3.05 g, 18.3 mmol) was added. The mixture was stirred at 60 °C for approximately 5 hours. After the reaction was complete, the mixture was directly concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE / EA=3 / 1) to give the white solid product, 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I103 (1.7 g, 94.4%).

[0332] The product was confirmed by LCMS.

[0333] Step 6 methyl 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((5-Bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I103 (1.2 g, 2.41 mmol) was dissolved in DCM / HO (15 mL / 3 mL). DDQ (1.0 g, 3.61 mmol) was added portionwise at 0 °C and the reaction mixture was stirred for 30 min. After the reaction was completed, water (100 mL) was added to the reaction mixture and extracted with DCM (30 mL x 2). The combined organic phases were washed with saturated sodium bicarbonate (30 mL), water (20 mL) and 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 flash column chromatography (PE / EA=2 / 1) to obtain the white solid product 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I104 (0.45 g, 53.7% yield).

[0334] The product was confirmed by LCMS.

[0335] Step 7 methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((5-Bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (344 mg, 2.42 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (392 mg, 2.42 mmol) was added and the mixture was stirred for 30 minutes, then stirred at room temperature for 1 hour. DMSO (10 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I104 (600 mg, 1.73 mmol) and potassium carbonate (477 mg, 3.46 mmol) were added, and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (30 mL) and 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 column chromatography (DCM / MeOH=10 / 1) to obtain the white solid product 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I105 (600 mg, 67.4% yield).

[0336] The product was confirmed by LCMS.

[0337] Step 8 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I105 (600 mg, 1.17 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L). The mixture was sealed and reacted at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T022 (50 mg, 8.6% yield).

[0338] The product was confirmed by LCMS, H-NMR and C-NMR.

[0339] 1 H NMR (400 MHz, CDCl3) δ: 10.90 (s, 1H), 7.73 (s, 1H), 7.21 (s, 1H), 6.42 (s, 1H), 5.72 (s, 1H), 5.42 (s, 2H), 3.89 (s, 3H), 3.31-3.32 (m, 2H), 2.47-2.53 (m, 6H), 2.10 (s, 2H), 1.83-1.87(m, 4H), 1.62-1.65 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ: 169.60, 165.86, 161.55, 154.02, 147.95, 113.99, 108.59, 63.72, 55.89, 53.93, 40.78, 40.57, 37.63, 28.35, 28.27, 28.13, 28.02, 26.77, 23.60, 23.41. Example 12: Synthesis of Compound T023 The synthetic route is as follows: [ka] Step 1 methyl3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butyloxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylic acid methyl ester To a solution of 3-(4-bromo-2,6-difluorophenoxy)-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid methyl ester I178 (300 mg, 0.68 mmol) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate I106 (208 mg, 0.75 mmol) in THF (30 mL) was added LiHMDS (1 M, 1.4 mL, 1.4 mmol) at 0°C, and the mixture was reacted with stirring at 0°C for 0.5 hours, and then at room temperature for another 0.5 hours with stirring. The reaction mixture was poured into water (30 mL), and the mixture was separated and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA=3 / 1) to give the yellow solid product 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butyloxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylic acid methyl ester I107 (22.5 mg, 5% yield).

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

[0341] 1H NMR (400 MHz, CDCl3) δ: 10.80 (s, 1H), 8.11 (d, 1H, J=2.4Hz), 7.36-7.39 (m, 1H), 7.14-7.18 (m, 2H), 6.92 (d, 1H, J=8.8Hz), 5.48 (s, 2H), 3.84 (s, 3H), 3.62-3.64 (m, 4H), 3.11-3.13 (m, 4H), 1.52 (s, 9H). Step 2 tert-butyl4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino) pyridine -3-yl)piperazine-1-carboxylate 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester 3-((4-Bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butyloxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylic acid methyl ester I107 (110 mg, 0.17 mmol) was dissolved in methanol (1 mL) and NH3 / MeOH (9 mL, 10 mol / L). The mixture was sealed at 60 °C and reacted for 72 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (PE / EA=3 / 1) to give the yellow solid product 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester I108 (50.0 mg, 46% yield).

[0342] The product was confirmed by LCMS and H-NMR.

[0343] 1H NMR (400 MHz, CDCl3) δ: 11.52 (s, 1H), 8.10 (d, 1H, J=2.4Hz), 7.36-7.39 (m, 1H), 7.18-7.19 (m, 2H), 7.02 (s, 1H), 6.94 (d, 1H, J=8.4Hz), 5.56 (s, 2H), 5.29 (s, 1H), 3.61-3.64 (m, 4H), 3.10-3.12 (m, 4H), 1.58 (s, 9H). Step 3 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide 4-(6-((3-((4-Bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester I108 (80.0 mg, 0.13 mmol) was dissolved in HCl / MeOH (5 mL, 8 mol / L), and the mixture was reacted for 1.0 hour with stirring at 25 °C. The reaction mixture was concentrated under reduced pressure, and the residue was added to water (10 mL) and adjusted to pH 9.0 with aqueous sodium carbonate. The mixture was separated and extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH=20 / 1) to give the white solid product 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide T023 (27.0 mg, 40% yield).

[0344] The product was confirmed by LCMS, H-NMR and C-NMR.

[0345] 1 H NMR (400 MHz, CDCl3) δ: 11.48 (s, 1H), 8.09 (d, 1H, J=2.8Hz), 7.34-7.37 (m, 1H), 7.18-7.19 (m, 2H), 7.02 (s, 1H), 6.93 (d, 1H, J=8.8Hz), 5.56 (s, 2H), 5.31(s, 1H), 3.13-3.14 (m, 4H), 3.08-3.09 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ: 168.67, 166.37, 161.41, 144.65, 142.87, 134.04, 128.04, 115.87, 115.78, 115.58, 111.71, 111.34, 95.37, 57.51, 57.47, 50.98, 46.01. Example 13: Synthesis of Compound T024 The synthetic route is as follows: [ka] Step 1 6-aminopyridin-3-ol 6-aminopyridin-3-ol 5-Methoxypyridin-2-amine (2.8 g, 22.6 mmol) was dissolved in 48% aqueous HBr (15 mL) and the reaction mixture was refluxed for 12 hours with stirring. The reaction mixture was cooled to room temperature, poured into cold water (20 mL), adjusted to pH 7-8 with aqueous sodium carbonate, and extracted with ethyl acetate (40 mL x 10). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 6-aminopyridin-3-ol I109 (1.3 g, 52.3% yield) as a black oil.

[0346] The product was confirmed by LCMS and HNMR.

[0347] 1H NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 7.50 (dd, 1H, J=3.2, 0.8Hz), 6.91 (dd, 1H, J=8.8, 3.2Hz), 6.34 (dd, 1H, J=8.8, 0.8Hz), 5.19 (s, 2H). Step 2 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-amine 5-(2-pyrrolidin-1-ylethoxy)pyridin-2-amine 6-Aminopyridin-3-ol I109 (1.3 g, 11.8 mmol) was dissolved in DMF (15 mL), and 1-(2-chloroethyl)pyrrolidine hydrochloride (2.0 g, 11.8 mmol) and sodium hydroxide (1.9 g, 47.2 mmol) were added. The reaction mixture was stirred at 65 °C for 2.0 h. The reaction mixture was cooled to room temperature, poured into brine (40 mL), and extracted with DCM / MeOH = 10 / 1 (v / v, 30 mL x 10). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give the black solid product, 5-(2-pyrrolidin-1-ylethoxy)pyridin-2-amine I110 (1.3 g, 53.1% yield).

[0348] The product was confirmed by LCMS and HNMR.

[0349] 1 H NMR (400 MHz, CDCl3) δ: 7.81 (d, 1H, J=2.8Hz), 7.13 (dd, 1H, J=8.8, 3.2Hz), 6.48 (d, 1H, J=8.8Hz), 4.19 (s, 2H), 4.06 (t, 2H, J=6.0Hz), 2.87 (t, 2H, J=6.0Hz), 2.60-2.63 (m, 4H), 1.80-1.83 (m, 4H). Step 3 methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-carboxylate 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester To a solution of 3-(4-bromo-2,6-difluorophenoxy)-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid methyl ester I178 (300 mg, 0.68 mmol) and 5-(2-pyrrolidin-1-ylethoxy)pyridin-2-amine I110 (155 mg, 0.75 mmol) in THF (30 mL) was added LiHMDS (1.4 mL, 1.4 mmol, 1 mol / L) dropwise at 0 °C. The mixture was stirred at 0 to 10°C for 1.0 hour, poured into aqueous NH4Cl (40 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give the white solid product, 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester I111 (18 mg, 4.8% yield).

[0350] The product was confirmed by LCMS and H-NMR.

[0351] 1H NMR (400 MHz, CDCl3) δ: 10.81 (s, 1H), 8.14 (d, 1H, J=2.8Hz), 7.36 (dd, 1H, J=8.8, 2.8Hz), 7.16 (d, 1H, J=6.8Hz), 6.92 (d, 1H, J=8.8Hz), 5.48 (s, 2H), 4.19 (t, 2H, J=6.0Hz), 2.96 (t, 2H, J=5.6Hz), 2.68 (m, 4H), 1.85-1.87 (m, 4H). Step 4 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-carboxamide 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide 3-(4-Bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester I111 (110 mg, 0.19 mmol) was dissolved in NH3 / MeOH (5 mL, 10 mol / L) and THF (1 mL). The mixture was sealed at 60 °C and reacted for 72 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give the white solid product, 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide T024 (21 mg, 19.6% yield).

[0352] The product was confirmed by LCMS, H-NMR and C-NMR.

[0353] 1H NMR (400 MHz, CDCl3) δ: 11.53 (s, 1H), 8.13 (d, 1H, J =2.8Hz), 7.35 (dd, 1H, J =8.8, 2.8Hz), 7.18-7.20 (m, 2H), 7.02 (s, 1H), 6.93 (d, 1H, J =8.8Hz), 5.56 (s, 2H), 5.32 (s, 1H), 4.19 (t, 2H, J =5.6 Hz), 2.96 (t, 2H, J =5.6 Hz), 2.69 (m, 4H), 1.86 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ: 168.80, 166.37, 162.93, 161.40, 150.34, 145.27, 132.01, 126.74, 123.22, 115.86, 115.84, 115.59, 115.57, 111.70, 95.55, 68.10, 57.56, 57.53, 57.49, 55.03, 54.71, 23.50. Example 14: Synthesis of Compound T026 The synthetic route is as follows: [ka] Step 1 5-(bromomethyl)benzofuran 5-(Bromomethyl)benzofuran (1-Benzofuran-5-yl)methanol (3.0 g, 20.3 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. PBr (8.21 g, 30.4 mmol) was added and the reaction mixture was stirred at room temperature for approximately 2 hours. After the reaction was complete, the reaction mixture was poured into water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the yellow oily liquid product, 5-(bromomethyl)benzofuran I117 (2.5 g, crude product).

[0354] The product was confirmed by LCMS.

[0355] Step 2 methyl 3-(benzofuran-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-(Benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.5 g, 6.33 mmol) and potassium carbonate (1.75 g, 12.7 mmol) were dissolved in DMF (10 mL). 5-(Bromomethyl)benzofuran I117 (1.33 g, 6.33 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 3 / 1) to give the white solid product, 3-(benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I118 (1.5 g, 65.2% yield).

[0356] The product was confirmed by LCMS and H-NMR.

[0357] 1 H NMR (400 MHz, DMSO-d6) δ: 8.03 (d, 1H, J=1.6Hz), 7.79 (s, 1H), 7.64 (d, 1H, J=8.4Hz), 7.44 (dd, 1H, J=8.8, 1.2Hz), 7.00 (d, 1H, J=1.2Hz), 5.58 (s, 2H), 3.88 (s, 3H), 3.61 (s, 3H). Step 3 methyl 3-(benzofuran-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-(Benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-(Benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I118 (2 g, 5.44 mmol) was dissolved in THF (50 mL), and 2,4-dimethoxybenzylamine (4.0 g, 24 mmol) was added. The reaction mixture was stirred at 65 °C for 6 hours. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography (PE / EA = 5 / 1) to give the yellow solid product, 3-(benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I119 (2.0 g, 81.0% yield).

[0358] The product was confirmed by LCMS.

[0359] Step 4 methyl 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylate 5-Amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester 3-(Benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I119 (1.5 g, 3.30 mmol) was dissolved in DCM / HO (20 mL / 4 mL). DDQ (1.37 g, 4.95 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 20 min. After the reaction was complete, water (10 mL) was added to the reaction mixture, washed with saturated aqueous sodium bicarbonate (25 mL), and the organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1) to give the yellow solid product, 5-amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester I120 (0.45 g, 45% yield).

[0360] The product was confirmed by LCMS.

[0361] Step 5 methyl 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-(Benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (392 mg, 2.76 mmol) was dissolved in anhydrous THF (10 mL) and cooled to 0 °C under nitrogen gas protection. CDI (448 mg, 2.76 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (10 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester I120 (600 mg, 1.97 mmol) and potassium carbonate (545 mg, 3.95 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (30 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow oily liquid product 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I121 (600 mg, 64.4% yield).

[0362] The product was confirmed by LCMS.

[0363] Step 6 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-(Benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I121 (600 mg, 1.27 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was reacted at 60 °C for 16 hours under a sealed condition. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T026 (60 mg, 10.5% yield).

[0364] The product was confirmed by LCMS, H-NMR and C-NMR.

[0365] 1 H NMR (400 MHz, CD3OD) δ: 7.78-7.79 (m, 2H), 7.53 (d, 1H, J=8.8Hz), 7.44 (d, 1H, J=8.4Hz), 6.87 (d, 1H, J=1.2Hz), 5.54 (s, 2H), 3.25 (t, 2H, J=6.0Hz), 2.49-2.57 (m, 6H), 1.82 (s, 4H), 1.58-1.60 (m, 4H). 13 C NMR (100 MHz, CD3OD) δ: 171.20, 168.32, 164.57, 157.42, 157.17, 148.27, 133.23, 130.22, 127.22, 123.83, 113.36, 108.68, 99.83, 72.81, 58.17, 56.00, 41.95, 29.90, 27.88, 25.18. Example 15: Synthesis of Compound T027 The synthetic route is as follows: [ka] Step 1 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene 4-(Bromomethyl)-1-(difluoromethoxy)-2-fluorophenyl [4-(difluoromethoxy)-3-fluorophenyl]methanol (3.0 g, 15.6 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. PBr (6.33 g, 23.4 mmol) was added and the reaction mixture was stirred at room temperature for approximately 3 hours. After the reaction was complete, the reaction mixture was added to water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic phases were washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorophenyl I122 (1.8 g crude product).

[0366] The product was confirmed by LCMS.

[0367] Step 2 methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.5 g, 6.33 mmol) and potassium carbonate (1.75 g, 12.7 mmol) were dissolved in DMF (20 mL), and 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorophenyl I122 (2.1 g, 8.24 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (20 mL) and 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 flash column chromatography (PE / EA=3 / 1) to obtain the white solid product, 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I123 (1.5 g, 57.7% yield).

[0368] The product was confirmed by LCMS and H-NMR.

[0369] 1 H NMR (400 MHz, DMSO-d6) δ: 7.55 (d, 1H, J=1.6Hz), 7.41-7.45 (m, 1H), 7.36-7.38 (m, 1H), 7.27 (t, 1H, J=73.2), 5.50 (s, 2H), 3.90 (s, 3H), 3.62 (s, 3H) Step 3 methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((4-(Difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I123 (2 g, 4.86 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (4.1 g, 24.6 mmol) was added. The reaction mixture was stirred at 60 °C for 6 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (PE / EA=5 / 1) to give the white solid product, 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I124 (2 g, 82.6% yield).

[0370] The product was confirmed by LCMS.

[0371] Step 4 methyl 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((4-(Difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I124 (2.3 g, 4.62 mmol) was dissolved in DCM / HO (20 / 4 mL), and DDQ (1.92 g, 6.93 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 20 min. After the reaction was completed, water (10 mL) was added to the reaction mixture, which was washed with saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA=5 / ) to obtain the yellow solid product 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I125 (0.6 g, 37.5% yield).

[0372] The product was confirmed by LCMS and H-NMR.

[0373] 1 H NMR (400 MHz, CDCl3) δ: 7.35 (dd, 1H, J=11.6, 1.6Hz), 7.23-7.26 (m, 2H), 6.57 (t, 1H, J=73.6Hz), 6.47 (s, 2H), 5.42 (s, 2H), 3.90 (s, 3H) Step 5 methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (343 mg, 2.42 mmol) was dissolved in anhydrous THF (10 mL) and cooled to 0 °C under nitrogen gas protection. CDI (491 mg, 2.42 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (10 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I125 (600 mg, 1.72 mmol) and potassium carbonate (476 mg, 3.45 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phase was washed successively with water (30 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow oily liquid product 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I126 (600 mg, 69.4% yield).

[0374] The product was confirmed by LCMS.

[0375] Step 6 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I126 (600 mg, 1.20 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was reacted at 60 °C for 16 hours under a sealed condition. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T027 (60 mg, 10.3% yield).

[0376] The product was confirmed by LCMS, H-NMR and C-NMR.

[0377] 1 H NMR (400 MHz, CD3OD) δ: 7.32-7.43 (m, 3H), 6.86 (t, 1H, J=73.6Hz), 5.48 (s, 2H), 3.26 (t, 2H, J=6.0Hz), 2.51-2.60 (m, 6H), 1.81-1.84 (m, 4H), 1.59-1.63 (m, 4H). 13 C NMR (100 MHz, CD3OD) δ: 168.97, 165.82, 161.67, 154.99, 154.75, 152.53, 135.80, 135.74, 124.41, 124.37, 122.18, 118.87, 116.66, 116.46, 116.28, 113.67, 97.33, 68.51, 55.73, 53.57, 39.53, 27.45, 25.43, 22.74. Example 16: Synthesis of Compound T028 The synthetic route is as follows: [ka] Step 1 methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((3-Methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (500 mg, 2.1 mmol) and potassium carbonate (580 mg, 4.2 mmol) were dissolved in DMF (5 mL), and 1-(bromomethyl)-3-methoxybenzene I127 (420 mg, 2.1 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture, and the filter cake was dried to give the white solid product, 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I128 (438 mg, 58.4% yield).

[0378] The product was confirmed by LCMS and H-NMR.

[0379] 1 H NMR (400 MHz, CDCl3) δ: 7.32 (t, 1H, J=8.0Hz), 7.03-7.06 (m, 2H), 6.90 (dd, 1H, J=8.4, 2.0Hz), 5.49 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H). Step 2 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((3-Methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I128 (0.5 g, 1.4 mmol) was dissolved in THF (10 mL), 2,4-dimethoxybenzylamine (2.3 g, 14 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and added to cold water (40 mL). The solid was filtered and dried to give the yellow solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I129 (500 mg, crude product).

[0380] The product was confirmed by LCMS.

[0381] Step 3 methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I129 (450 mg, 1.0 mmol) was dissolved in DCM / HO (5 / 1 mL). DDQ (920 mg, 4.04 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was directly concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1 to 3 / 1) to give the white solid product, 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I130 (200 mg, 67.1% yield).

[0382] The product was confirmed by LCMS.

[0383] Step 4 methyl 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((3-Methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (102 mg, 0.72 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (117 mg, 0.72 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (6 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I130 (150 mg, 0.51 mmol) and potassium carbonate (141 mg, 1.02 mmol) were added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (5 mL) was added to the reaction mixture, which was then filtered to leave the solid. The filter cake was dried to obtain the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow solid product 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I131 (75 mg, 31.8% yield).

[0384] The product was confirmed by LCMS and H-NMR.

[0385] 1H NMR (400 MHz, CDCl3) δ: 10.22 (s, 1H), 8.24 (s, 1H), 7.28-7.32 (m, 1H), 7.04-7.07 (m, 2H), 6.87 (d, 1H, J=7.6Hz), 5.44 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.33 (s, 2H), 2.61-2.64 (m, 4H), 2.54-2.56 (m, 2H),1.90 (s, 4H), 1.26-1.30 (m, 4H). Step 5 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3-Methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I131 (100 mg, 0.22 mmol) was dissolved in NH3 / MeOH (3 mL, 9 mol / L), and the mixture was reacted at 60 °C for 16 hours under a sealed condition. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T028 (15 mg, 15.4% yield).

[0386] The product was confirmed by LCMS, H-NMR and C-NMR.

[0387] 1H NMR (400 MHz, CDCl3) δ: 10.94 (br s, 1H), 7.82 (br s, 1H), 7.33 (t, 1H, J=8.0Hz), 7.19 (s, 1H), 7.03 (d, 1H, J=7.6Hz), 7.00 (d, 1H, J=2.4Hz), 6.92 (dd, 1H, J=8.0, 2.4Hz), 5.48 (s, 1H), 5.45 (s, 2H), 3.84 (s, 3H), 3.34 (s, 2H), 2.61-2.69 (m, 6H), 1.92 (s, 4H), 1.71 (s, 4H). 13 C NMR (100 MHz, CDCl3) δ: 169.58, 165.95, 161.89, 159.84, 154.08, 137.46, 129.83, 120.52, 113.93, 113.91, 70.34, 55.85, 55.29, 53.91, 28.11, 26.61, 23.40. Example 17: Synthesis of Compound T029 The synthetic route is as follows: [ka] Step 1 methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (500 mg, 2.1 mmol) and potassium carbonate (580 mg, 4.2 mmol) were dissolved in DMF (5 mL), and 4-(bromomethyl)-2-fluoro-1-methoxybenzene I132 (462 mg, 2.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture, which was then filtered to remove the solid. The filter cake was dried to give the crude yellow solid product, 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I133 (500 mg, 63.2% yield).

[0388] The product was confirmed by LCMS and H-NMR.

[0389] 1 H NMR (400 MHz, CDCl3) δ: 7.18-7.25 (m, 2H), 6.98 (t, 1H, J=8.4Hz), 5.42 (s, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.49 (s, 3H). Step 2 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((3-Fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I133 (0.58 g, 1.5 mmol) was dissolved in THF (20 mL), 2,4-dimethoxybenzylamine (2.5 g, 15 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, added to water (40 mL), and filtered to leave a solid. After drying, a yellow solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I134 (550 mg, 77.0% yield), was obtained.

[0390] The product was confirmed by LCMS.

[0391] Step 3 methyl 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I134 (500 mg, 1.08 mmol) was dissolved in DCM / HO (5 / 1 mL). DDQ (983 mg, 4.32 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1 to 3 / 1) to give the yellow solid product, 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I135 (220 mg, 65.1% yield).

[0392] The product was confirmed by LCMS.

[0393] Step 4 methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole -4-carboxylate 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (108 mg, 0.76 mmol) was dissolved in anhydrous THF (6 mL) and cooled to 0 °C under nitrogen gas protection. CDI (123 mg, 0.76 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (6 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I135 (170 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (5 mL) was added to the reaction mixture, filtered to leave the solid, and dried to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow solid product 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I136 (100 mg, 38.4% yield).

[0394] The product was confirmed by LCMS and H-NMR.

[0395] 1H NMR (400 MHz, CDCl3) δ: 10.25 (s, 1H), 8.24 (s, 1H), 7.25-7.28 (m, 1H,), 7.17 (d, 1H, J=8.4Hz), 6.97 (t, 1H, J=8.4Hz), 5.37 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.32-3.33 (m, 2H), 2.60 (s, 4H), 2.52-2.55 (m, 2H),1.89-1.91 (m, 4H), 1.72 (s, 4H). Step 5 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I136 (140 mg, 0.28 mmol) was dissolved in NH3 / MeOH (3 mL, 9 mol / L). The mixture was sealed at 60 °C and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T029 (15 mg, 11.9% yield).

[0396] The product was confirmed by LCMS, H-NMR and C-NMR.

[0397] 1H NMR (400 MHz, CD3OD) δ: 7.25-7.29 (m, 2H), 7.13 (d, 1H, J=8.4Hz), 5.40 (s, 2H), 3.90 (s, 3H), 3.25-3.32 (m, 3H), 2.56-2.65 (m, 5H), 1.83-1.87(m, 4H), 1.61-1.62 (m, 4H). 13 C NMR (100 MHz, CD3OD) δ: 168.81, 165.86, 161.94,154.76, 150.90, 147.96, 129.14, 124.71, 124.67, 115.97, 115.79, 113.26, 69.17, 55.62, 55.32, 53.59, 39.41, 29.33, 27.38, 25.21, 22.72. Example 18: Synthesis of Compound T030 The synthetic route is as follows: [ka] Step 1 1-(bromomethyl)-2-fluoro-3-methoxybenzene 1-(Bromomethyl)-2-fluoro-3-methoxybenzene (2-Fluoro-3-methoxyphenyl)methanol (0.5 g, 3.2 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. PBr (1.0 g, 3.8 mmol) was added under nitrogen gas protection, and the reaction mixture was stirred at room temperature for approximately 1 h. After the reaction was complete, the mixture was directly concentrated under reduced pressure to give the crude white product 1-(bromomethyl)-2-fluoro-3-methoxybenzene I137 (1 g, crude).

[0398] The product was confirmed by LCMS.

[0399] Step 2 methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((2-Fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.8 g, 3.2 mmol) and potassium carbonate (1.8 g, 12.8 mmol) were dissolved in DMF (15 mL). 1-(Bromomethyl)-2-fluoro-3-methoxybenzene I137 (0.9 g, crude product) was added and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude white solid product, 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I138 (0.7 g, 58.3% yield).

[0400] The product was confirmed by LCMS and H-NMR.

[0401] 1 H NMR (400 MHz, CDCl3) δ: 7.08-7.77 (m, 2H), 6.95-7.05 (m, 1H), 5.57 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.49 (s, 3H). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((2-Fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I138 (0.7 g, 1.9 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (2.2 g, 13.3 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, added to water (40 mL), and filtered to remove the solid. The solid was washed with water (10 mL x 3) and dried to give the white solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I139 (0.6 g, 70.6% yield).

[0402] The product was confirmed by LCMS and H-NMR.

[0403] 1 H NMR (400 MHz, CDCl3) δ: 8.13 (br s, 1H), 7.15-7.19 (m, 2H), 7.09 (t, 1H, J=8.0Hz), 6.94 (t, 1H, J=8.0Hz), 6.45-6.49 (m, 2H), 5.52 (s, 2H), 4.29 (d, 2H, J=5.6Hz), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H). Step 4 methyl 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylic acid methyl ester I139 (0.4 g, 0.86 mmol) was dissolved in DCM / HO (12 / 2.4 mL), and DDQ (0.78 g, 3.4 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, water (25 mL) was added to the reaction mixture and extracted with dichloromethane (20 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 obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA=2 / 1) to obtain the yellow solid product, 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I140 (180 mg, 67.2% yield).

[0404] The product was confirmed by LCMS and H-NMR.

[0405] 1 H NMR (400 MHz, CDCl3) δ: 7.15-7.17 (m, 1H), 7.10-7.12 (m, 1H), 6.95 (d, 1H, J=1.2Hz), 6.45 (br s, 2H), 5.53 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H). Step 5 methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((2-Fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (116 mg, 0.82 mmol) was dissolved in anhydrous THF (6 mL) and cooled to 0 °C under nitrogen gas protection. CDI (132 mg, 0.82 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (6 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I140 (180 mg, 0.58) and potassium carbonate (160 mg, 1.16 mmol) were added and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was washed successively with water (30 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow solid product 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I141 (130 mg, 46.8% yield).

[0406] The product was confirmed by LCMS and H-NMR.

[0407] 1 H NMR (400 MHz, CDCl3) δ: 10.10 (br, 1H), 7.90 (br, 1H), 7.08-7.15 (m, 2H), 6.94 (d, 1H, J=1.6Hz), 5.53 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.33 (s, 2H), 2.68 (s, 4H), 2.60 (t, 2H, J=6.4Hz), 1.91-2.00 (m, 4H), 1.68-1.72 (m, 4H). Step 6 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I141 (180 mg, 0.37 mmol) was dissolved in NH3 / MeOH (6 mL, 9 mol / L), and the mixture was reacted at 60 °C in a sealed container for 72 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.HO=10 / 1 / 0.1) to give the white solid product, 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T030 (25 mg, 12.9% yield).

[0408] The product was confirmed by LCMS, H-NMR and C-NMR.

[0409] 1 H NMR (400 MHz, DMSO-d6) δ: 11.00 (s, 1H), 8.20 (s, 1H), 7.64 (s, 1H), 7.14-7.19 (m, 2H), 7.08-7.10 (m, 1H), 6.95 (s, 1H), 5.47 (s, 2H), 3.85 (s, 3H), 3.12 (d, 2H, J=5.6Hz), 2.37-2.40 (m, 6H), 1.64-1.68 (m, 4H), 1.46 (s, 4H). 13C NMR (100 MHz, DMSO-d6) δ: 168. 61, 164.82, 161.68, 154.51, 124.88, 124.38, 114.53, 97.81, 64.07, 56.52, 55.68, 54.04, 27.65, 26.11, 23.54. Example 19: Synthesis of Compound T032 The synthetic route is as follows: [ka] Step 1 1-(bromomethyl)-2,3-dimethoxybenzene 1-(Bromomethyl)-2,3-dimethoxybenzene (2,3-Dimethoxyphenyl)methanol (0.5 g, 2.97 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. PBr (0.27 g, 0.99 mmol) was added and the reaction mixture was stirred at 10 °C or less for approximately 1 hour. After the reaction was complete, the reaction mixture was poured into water (40 mL) and extracted with dichloromethane. The combined organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, 1-(bromomethyl)-2,3-dimethoxybenzene I147 (0.6 g, 87.3% yield), as a colorless oil.

[0410] The product was confirmed by LCMS and H-NMR.

[0411] 1 H NMR (400 MHz, CDCl3) δ: 7.05 (t, J = 8.0 Hz, 1H), 6.98 (dd, J = 7.6, 1.6 Hz, 1H), 6.90 (dd, J = 8.0, 1.6 Hz, 1H), 4.59 (s, 2H), 3.98 (s, 3H), 3.89 (s, 3H). Step 2 methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((2,3-Dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.51 g, 2.16 mmol) and potassium carbonate (0.90 g, 6.49 mmol) were dissolved in DMF (5 mL). 1-(Bromomethyl)-2,3-dimethoxybenzene I147 (0.6 g, 2.60 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction mixture, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to give the crude white solid product, 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I148 (0.6 g, 72.0% yield).

[0412] The product was confirmed by LCMS and H-NMR.

[0413] 1 H NMR (400 MHz, CDCl3) δ: 7.05-7.14 (m, 2H), 6.93-6.99 (m, 1H), 5.57 (s, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.50 (s, 3H). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((2,3-Dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I148 (0.5 g, 1.29 mmol) was dissolved in THF (5 mL), and 2,4-dimethoxybenzylamine (2.16 g, 12.9 mmol) was added. The reaction mixture was stirred at 65 °C for 1 hour. After completion of the reaction, the reaction mixture was added to water (30 mL) and filtered to obtain a solid. The filter cake was washed with water and dried to obtain a yellow solid product: 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I149 (0.54 g, 88.4% yield).

[0414] The product was confirmed by LCMS and H-NMR.

[0415] 1 H NMR (400 MHz, CDCl3) δ: 8.14 (t, J = 6.0 Hz, 1H), 7.15-7.21 (m, 2H), 7.09 (t, J = 7.9 Hz, 1H), 6.91 (dd, J = 8.1, 1.6 Hz, 1H), 6.44-6.51 (m, 2H), 5.49 (s, 2H), 3.90 (s, 3H), 3.90 (s, 3H), 3.87 (s, 3H), 3.81-3.83 (m, 6H). Step 4 methyl 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I149 (0.6 g, 1.26 mmol) was dissolved in DCM / HO (6 / 1.2 mL). DDQ (0.34 g, 1.52 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, neutral aluminum oxide was added to the reaction mixture, which was then concentrated under reduced pressure to remove most of the solvent. The crude product was purified by column chromatography (neutral aluminum oxide, PE / EA = 10 / 1 to 1 / 1) to give the white solid product, 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I150 (0.35 g, 85.3% yield).

[0416] The product was confirmed by LCMS and H-NMR.

[0417] 1 H NMR (400 MHz, CDCl3) δ: 7.18 (dd, J = 7.8, 1.6 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 8.1, 1.6 Hz, 1H), 6.38-6.49 (m, 2H), 5.51 (s, 2H), 3.90-3.91 (m, 6H), 3.85 (s, 3H). Step 5 methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((2,3-Dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (123 mg, 0.86 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (140 mg, 0.86 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I150 (200 mg, 0.62 mmol) and potassium carbonate (170 mg, 1.23 mmol) were added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to obtain the crude white solid product 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I151 (200 mg, 65.8% yield).

[0418] The product was confirmed by LCMS and H-NMR.

[0419] 1 H NMR (400 MHz, CDCl3) δ: 10.22 (br s, 1H), 8.20 (br s, 1H), 7.18 (dd, J= 7.7, 1.6 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H), 5.52 (s, 2H), 3.90-3.91 (m, 6H), 3.86 (s, 3H), 3.33 (d, J = 5.4 Hz, 2H), 2.47-2.63 (m, 6H), 1.84-1.96 (m, 4H), 1.68-1.74 (m, 4H). Step 6 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I151 (200 mg, 0.42 mmol) was dissolved in NH3 / MeOH (14 mL, 10 mol / L). The mixture was sealed at 60 °C and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.HO) to give the white solid product, 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T032 (27 mg, 13.9% yield).

[0420] The product was confirmed by LCMS, H-NMR and C-NMR.

[0421] 1 H NMR (400 MHz, CDCl3) δ: 10.91 (br s, 1H), 7.76 (br s, 1H), 7.25-7.29 (m, 1H), 7.09 (t, J= 7.8 Hz, 1H), 7.03 (dd, J = 7.8, 1.7 Hz, 1H), 6.96 (dd, J = 8.0, 1.7 Hz, 1H), 5.65 (s, 1H), 5.52 (s, 2H), 3.89-3.90 (m, 6H), 3.26-3.37 (m, 2H), 2.52-2.63 (m, 4H), 2.51 (t, 2H, J=6.4Hz), 1.74-1.92 (m, 4H), 1.58-1.73 (m, 4H). 13C NMR (100 MHz, CDCl3) δ: 169.46, 165.95, 162.04, 154.02, 152.80, 147.81, 129.68, 124.16, 121.94, 112.97, 97.39, 65.79, 61.08, 55.87, 55.81, 53.91, 40.56, 28.13, 26.73, 23.40. Example 20: Synthesis of Compound T033 The synthetic route is as follows: [ka] Step 1 5-(bromomethyl)-2-methoxypyridine 5-(Bromomethyl)-2-methoxypyridine (6-Methoxypyridin-3-yl)methanol (0.5 g, 3.6 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. PBr (1.1 g, 4.0 mmol) was added and the reaction mixture was stirred at room temperature for approximately 4 h. After completion of the reaction, the mixture was directly concentrated under reduced pressure to give the crude yellow solid product, 5-(bromomethyl)-2-methoxypyridine I152 (1.0 g, crude).

[0422] The product was confirmed by LCMS and used directly in the next reaction.

[0423] Step 2 methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((6-Methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.85 g, 3.6 mmol) and potassium carbonate (2.0 g, 14.4 mmol) were dissolved in DMF (15 mL). 5-(Bromomethyl)-2-methoxypyridine I152 (1.0 g, crude product) was added and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to obtain the crude white solid product, 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I153 (0.8 g, 61.5% yield).

[0424] The product was confirmed by LCMS and H-NMR.

[0425] 1 H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 7.72 (d, 2H, J=8.4Hz),6.79 (d, 2H, J=8.4Hz), 5.44 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.49 (s, 3H). Step 3 methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((6-Methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I153 (0.79 g, 2.2 mmol) was dissolved in THF (15 mL), and 2,4-dimethoxybenzylamine (0.6 g, 15.4 mmol) was added. The reaction mixture was stirred at 60 °C for 1 hour. After completion of the reaction, the reaction mixture was added to cold water (50 mL), filtered to obtain a solid, which was washed with water and dried to give the white solid product, 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I154 (0.7 g, 71.4% yield).

[0426] The product was confirmed by LCMS and H-NMR.

[0427] 1 H NMR (400 MHz, CDCl3) δ: 8.27 (d, 1H, J=2.4Hz), 8.13 (t, 1H, J=6.0Hz), 7.71 (dd, 1H, J=8.4, 2.4Hz), 7.18 (d, 1H, J=8.4Hz), 6.76 (d, 1H, J=8.4Hz), 6.44-6.49 (m, 2H), 5.36 (s, 2H), 4.28 (d, 1H, J=6.4Hz), 3.96 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H). Step 4 methyl 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I154 (0.67 g, 1.50 mmol) was dissolved in DCM / HO (25 / 5 mL), and DDQ (1.37 g, 6.02 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was added to saturated sodium bicarbonate (25 mL) and extracted with DCM (25 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA=1 / 1) to obtain the yellow solid product 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I155 (290 mg, 65.3% yield).

[0428] The product was confirmed by LCMS and H-NMR.

[0429] 1 H NMR (400 MHz, CDCl3) δ: 8.28 (d, 1H, J=2.4Hz), 7.72(dd, 1H, J=8.4, 2.4Hz), 6.77 (d, 1H, J=8.4Hz), 6.45 (s, 2H), 5.37 (s, 2H), 3.96 (s, 3H), 3.84 (s, 3H). Step 5 methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido) isothiazole-4-carboxylate 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (189 mg, 1.33 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (191 mg, 1.33 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I155 (280 mg, 0.95 mmol) and potassium carbonate (262 mg, 1.90 mmol) were added and the mixture was stirred at room temperature for 8 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL×3). The organic phase was 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1) to obtain the yellow solid product 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I156 (230 mg, 52.3% yield).

[0430] The product was confirmed by LCMS and H-NMR.

[0431] 1 H NMR (400 MHz, CDCl3) δ: 10.30 (br s, 1H), 8.28 (d, 1H, J=2.0Hz), 8.01 (br s, 1H), 7.71 (dd, 1H, J=8.4, 2.4Hz), 6.76 (d, 1H, J=8.8Hz), 5.37 (s, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.32 (s, 2H), 2.51-2.60 (m, 6H), 1.87-1.89 (m, 4H), 1.66-1.68 (m, 4H). Step 6 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide 3-((6-Methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I156 (220 mg, 0.47 mmol) was dissolved in NH3 / MeOH (10 mL, 10 mol / L) in a microwave tube, and the mixture was reacted at 60 °C in a sealed container for 72 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product, 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide T033 (23 mg, 10.8% yield).

[0432] The product was confirmed by LCMS, H-NMR and C-NMR.

[0433] 1 H NMR (400 MHz, CD3OD) δ: 8.29 (d, 1H, J=2.4Hz), 7.86 (dd, 1H, J=8.4, 2.0Hz), 6.84 (d, 1H, J=8.8Hz), 5.44 (s, 2H), 3.93 (s, 3H), 3.26 (t, 2H, J=6.8Hz), 2.69 (s, 4H), 2.62 (t, 2H, J=7.2Hz), 1.84-1.88 (m, 4H), 1.59-1.62 (m, 4H). 13C NMR (100 MHz, CD3OD) δ: 168.85, 165.81, 164.44, 161.84, 154.76, 147.24, 139.88, 125.06, 110.34, 67.10, 55.43, 53.61, 52.77, 39.23, 27.26, 24.84, 22.71. Example 21: Synthesis of Compound T035 The synthetic route is as follows: [ka] Step 1 6-(bromomethyl)-2-methylbenzo[d]oxazole 6-(Bromomethyl)-2-methylbenzo[d]oxazole (2-Methyl-1,3-benzoxazol-6-yl)methanol (1 g, 6.1 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. PBr (1.66 g, 6.1 mmol) was added and the reaction mixture was stirred at room temperature for approximately 30 min. After completion of the reaction, the mixture was directly concentrated under reduced pressure to give the crude yellow solid product 6-(bromomethyl)-2-methylbenzo[d]oxazole I163 (1.1 g, crude).

[0434] The product was confirmed by LCMS.

[0435] Step 2 methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1 g, 4.42 mmol) and potassium carbonate (0.61 g, 4.42 mmol) were dissolved in DMF (20 mL). 6-(bromomethyl)-2-methylbenzo[d]oxazole I163 (1.05 g, 4.42 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the solid was filtered and dried to give the crude yellow solid 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I164 (1 g, 59.2% yield).

[0436] The product was confirmed by LCMS and H-NMR.

[0437] 1 H NMR (400 MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.69 (s, 1H, J=8.0Hz), 7.47 (s, 1H, J=0.8Hz), 5.60 (s, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 2.62 (s, 3H). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((2-Methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I164 (1 g, 2.61 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (4.37 g, 26.15 mmol) was added. The reaction mixture was stirred at 65 °C for 1 hour. After completion of the reaction, the reaction solution was added to water (30 mL), filtered, and the solid was dried to give the yellow solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I165 (550 mg, 77% yield).

[0438] The product was confirmed by LCMS and H-NMR.

[0439] 1 H NMR (400 MHz, DMSO-d6) δ: 8.41 (t, 1H, J=6.0Hz), 7.70 (s, 1H), 7.63 (d, 1H, J=8.0Hz), 7.38-7.40 (m, 1H), 7.16 (d, 1H, J=8.0Hz), 6.59 (d, 1H, J=2.4Hz), 6.50 (dd, 1H, J=8.0, 2.0Hz), 5.43 (s, 2H), 4.27 (d, 1H, J=6.0Hz), 3.82 (s, 3H), 3.73-3.74 (m, 6H), 2.60 (s, 3H). Step 4 methyl 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I165 (1 g, 2.13 mmol) was dissolved in DCM / HO (10 / 2 mL), and DDQ (1.93 g, 8.52 mmol) was added portionwise at 0 °C. The reaction was allowed to proceed with stirring for 1 h. After the reaction was completed, water (100 mL) was added to the reaction mixture and extracted with DCM (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 5 / 1 to 2 / 1) to obtain the yellow solid product 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I166 (300 mg, 44.1% yield).

[0440] The product was confirmed by LCMS and H-NMR.

[0441] 1 H NMR (400 MHz, DMSO-d6) δ: 7.92 (s, 2H), 7.73 (s, 1H), 7.65 (d, 1H, J=7.6Hz), 7.40-7.43 (m, 1H), 6.64-6.70 (m, 1H), 5.44 (s, 2H), 3.72 (s, 3H), 2.62 (s, 3H). Step 5 methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (134 mg, 0.94 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (300 mg, 0.94 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I166 (300 mg, 0.94 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude yellow solid product 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I167 (200 mg, 43.7% yield).

[0442] The product was confirmed by LCMS.

[0443] Step 6 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido) isothiazole-4-carboxamide 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I167 (200 mg, 0.41 mmol) was dissolved in NH3 / MeOH (5 mL, 9 mol / L). The mixture was sealed and reacted at 60 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.HO) to give the white solid product, 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T035 (15 mg, 11.9% yield).

[0444] The product was confirmed by LCMS, H-NMR and C-NMR.

[0445] 1 H NMR (400 MHz, CDCl3) δ: 10.96 (br s, 1H), 7.75 (br s, 1H), 7.68 (d, 1H, J=8Hz), 7.56 (s, 1H), 7.40-7.42 (m, 2H), 7.13 (s, 1H), 5.57 (s, 2H), 5.53 (s, 1H), 3.34 (s, 2H), 2.67-2.71 (s, 3H), 2.57 (s, 3H), 1.92 (s, 4H), 1.71 (s, 4H). 13 C NMR (100 MHz, CDCl3) δ: 169.62, 165.97, 164.74, 161.73, 154.15, 151.07, 141.83, 132.67, 124.74, 119.51, 110.55, 70.40, 55.81, 53.88, 40.91 28.00, 26.43, 23.36, 14.59, 1.02. Example 22: Synthesis of Compound T036 The synthetic route is as follows: [ka] Step 1 1-(bromomethyl)-4-ethoxybenzene 1-(Bromomethyl)-4-ethoxybenzene (4-Ethoxyphenyl)methanol (500 mg, 3.29 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. PBr3 (296 mg, 1.10 mmol) was added and the reaction mixture was stirred at 10 °C for approximately 1 h. After the reaction was complete, the mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, 1-(bromomethyl)-4-ethoxybenzene I168 (600 mg, 84.9% yield), as a yellow oily liquid.

[0446] The product was confirmed by LCMS and H-NMR.

[0447] 1 H NMR (400 MHz, CDCl3) δ: 7.32-7.35 (m, 2H), 6.86-6.89 (m, 2H), 4.53 (s, 2H), 4.06 (q, 2H, J=7.2Hz), 1.44 (t, 3H, J=7.2Hz). Step 2 methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (500 mg, 2.11 mmol) and potassium carbonate (74 mg, 6.32 mmol) were dissolved in DMF (5 mL). 1-(Bromomethyl)-4-ethoxybenzene I168 (544 mg, 2.53 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to give the crude off-white solid product, 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I169 (610 mg, 77.9% yield).

[0448] The product was confirmed by LCMS and H-NMR.

[0449] 1 H NMR (400 MHz, CDCl3) δ: 7.40 (d, 2H, J=8.8Hz), 6.92 (d, 2H, J=8.8Hz), 5.44 (s, 2H), 4.07 (q, 2H, J=7.2Hz), 3.96 (s, 3H), 3.48 (s, 3H), 1.44 (t, 3H, J=7.2Hz). Step 3 methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate 5-((2,4-Dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((4-Ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I169 (500 mg, 1.35 mmol) was dissolved in THF (5 mL), and 2,4-dimethoxybenzylamine (2.25 g, 13.5 mmol) was added. The reaction mixture was stirred at 65°C for 1 hour. After completion of the reaction, the reaction mixture was added to water (20 mL) and extracted with ethyl acetate (50 mLx3). The combined organic phases were washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA=10 / 1-5 / 1-3 / 1) to obtain the pale white solid product, 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I170 (550 mg, 89.1% yield).

[0450] The product was confirmed by LCMS and H-NMR.

[0451] 1 H NMR (400 MHz, CDCl3) δ: 8.13 (t, 1H, J=6.0Hz), 7.41 (d, 2H, J=2.8Hz), 7.18 (d, 1H, J=8.4Hz), 6.89-6.92 (m, 2H), 6.45-6.49 (m, 2H), 5.37 (s, 2H), 4.29 (d, 2H, J=6.0Hz), 4.06 (q, 2H, J=7.2Hz), 3.86(s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 1.43 (t, 3H, J=6.8Hz). Step 4 methyl 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I170 (550 mg, 1.20 mmol) was dissolved in DCM / HO (11 / 2.2 mL), and DDQ (817 mg, 3.60 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, water (40 mL) was added to the reaction mixture, the solid was filtered and discarded, and the filtrate was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA=20 / 1-10 / 1-5 / 1-1 / 1) to obtain the yellow solid product 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I171 (290 mg, 78.4% yield).

[0452] The product was confirmed by LCMS and H-NMR.

[0453] 1 H NMR (400 MHz, CDCl3) δ: 7.40 (d, 2H, J=8.8Hz), 6.90-6.92 (m, 2H), 6.44 (s, 2H), 5.38 (s, 2H), 4.06 (q, 2H, J=7.2Hz), 3.85 (s, 3H), 1.44 (t, 3H, J=7.2Hz). Step 5 methyl 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (129 mg, 0.91 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0 °C under nitrogen gas protection. CDI (147 mg, 0.91 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I171 (200 mg, 0.65 mmol) and potassium carbonate (179 mg, 1.30 mmol) were added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to obtain the crude pale white solid product 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I172 (180 mg, 58.2% yield).

[0454] The product was confirmed by LCMS and H-NMR.

[0455] 1 H NMR (400 MHz, CDCl3) δ: 10.22 (br s, 1H), 8.18 (br s, 1H), 7.41 (d, 2H, J=8.8Hz), 6.91 (d, 1H, J=8.8Hz), 5.39 (s, 2H), 4.06 (q, 2H, J=7.2Hz), 3.96 (s, 3H), 3.33 (d, 2H, J=5.2Hz), 2.52-2.64 (m, 6H), 1.89-1.91 (m, 4H), 1.68 (s, 4H), 1.44 (t, 3H, J=7.2Hz). Step 6 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide In a microwave tube, 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I172 (100 mg, 0.21 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L). The mixture was sealed at 60 °C and reacted for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.HO (25%) = 100 / 10 / 1) to give the white solid product, 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T036 (30 mg, 31.0% yield).

[0456] The product was confirmed by LCMS, H-NMR and C-NMR.

[0457] 1 H NMR (400 MHz, CDCl3) δ: 10.91 (s, 1H), 7.82 (s, 1H), 7.38 (d, 2H, J=8.8Hz), 7.18 (s, 1H), 6.92 (d, 2H, J=8.4Hz), 5.60 (s, 1H), 5.39 (s, 2H), 4.06 (q, 2H, J=7.2Hz), 3.33 (s, 2H), 2.51-2.58 (m, 6H), 1.86 (s, 4H), 1.67-1.68 (m, 4H), 1.44 (t, 3H, J=7.2Hz). 13 C NMR (100 MHz, CDCl3) δ: 169.48, 165.91, 162.09, 159.27, 153.99, 130.23, 127.84, 114.63, 70.33, 63.52, 55.56, 53.90, 40.58, 28.15, 26.72, 23.41, 14.82. Example 23: Synthesis of Compound T042 The synthetic route is as follows: [ka] Step 1 2,3-dihydrobenzofuran-6-carboxylic acid 2,3-Dihydrobenzofuran-6-carboxylic acid Benzofuran-6-carboxylic acid (4 g, 24.67 mmol) and Pd / C (899 mg) were dissolved in methanol (50 mL) and reacted under hydrogen gas (20 psi) at room temperature with stirring for 16 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the crude white solid product, 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 91.4% yield).

[0458] The product was confirmed by LCMS and H-NMR.

[0459] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, 1H, J = 7.6, 1.6 Hz), 7.32 (d, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 1.2 Hz), 4.57 (t, 2H, J = 8.8 Hz), 3.23 (t, 2H, J = 8.8 Hz). Step 2 (2,3-dihydrobenzofuran-6-yl)methanol (2,3-Dihydrobenzofuran-6-yl)methanol Under nitrogen gas protection, 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 22.54 mmol) was dissolved in anhydrous THF (50 mL). BH3.Me2S (10 M, 5.63 mL, 56.3 mmol) was added in an ice-water bath. The reaction temperature of the mixture was raised to 60 °C and the mixture was stirred for 16 hours. The reaction mixture was poured into methanol (100 mL) and concentrated under reduced pressure to give the crude product, (2,3-dihydrobenzofuran-6-yl)methanol I194 (3.3 g, 97.49% yield), as a colorless liquid.

[0460] The product was confirmed by LCMS and used directly in the next reaction.

[0461] Step 3 6-(bromomethyl)-2,3-dihydrobenzofuran 6-(Bromomethyl)-2,3-dihydrobenzofuran (2,3-Dihydrobenzofuran-6-yl)methanol I194 (3.3 g, 21.97 mmol) was dissolved in DCM (50 mL) and cooled to 0 °C. PBr3 (8.92 g, 32.96 mmol) was added and the reaction mixture was stirred at room temperature for approximately 1 h. After the reaction was complete, the mixture was added to cold saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude white product 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (4 g, 85.3% yield).

[0462] The product was confirmed by LCMS.

[0463] Step 4 methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMF (10 mL), and 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (0.99 g, 4.64 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mLx3). The organic phase was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA=10 / 1) to give the white solid product 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I196 (1.2 g, 77.1% yield).

[0464] The product was confirmed by LCMS and H-NMR.

[0465] 1 H NMR (400 MHz, DMSO-d6) δ: 7.24 (d, 1H, J=7.6Hz), 6.93 (d, 1H, J=7.6Hz), 6.86 (s, 1H), 5.41 (s, 2H), 4.53 (t, 2H, J=8.8Hz), 3.88 (s, 3H), 3.61 (s, 3H), 3.17 (t, 2H, J=8.8Hz). Step 5 methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino) isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I196 (1.4 g, 3.79 mmol) was dissolved in THF (25 mL), and 2,4-dimethoxybenzylamine (3.17 g, 18.95 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water (30 mL), adjusted to pH 5, and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the white solid product, 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I197 (1.3 g, 75.1% yield).

[0466] The product was confirmed by LCMS and H-NMR.

[0467] 1H NMR (400MHz, CDCl3): δ (ppm) 8.15 (t, 1H, J=5.6Hz), 7.18 (d, 2H, J=8.4Hz), 6.94 (t, 2H, J=3.2Hz), 6.45-6.49 (m, 2H), 5.38 (s, 2H), 4.59 (t, 2H, J=8.8Hz), 4.29 (d, 2H, J=6.0Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.82 (s, 3H), 3.22 (t, 2H, J=8.8Hz). Step 6 methyl 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I197 (1.64 g, 3.59 mmol) was dissolved in DCM / HO (15 / 3 mL), and DDQ (1.22 g, 5.39 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 20 min. After the reaction was completed, water (30 mL) was added to the reaction mixture and extracted with DCM (30 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by chromatography column (PE / EA=10 / 1-3 / 1) to obtain the yellow solid product 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I198 (0.4 g, 36.4% yield).

[0468] The product was confirmed by LCMS.

[0469] Step 7 methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (390 mg, 2.74 mmol) was dissolved in anhydrous THF (10 mL) and cooled to 0 °C under nitrogen gas protection. CDI (445 mg, 2.74 mmol) was added and the mixture was stirred at room temperature for 1 hour. DMSO (10 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I198 (0.6 g, 1.96 mmol) and potassium carbonate (541 mg, 3.92 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water (30 mL) and 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 preparative thin-layer chromatography (DCM / MeOH=10 / 1, 1% NH3.HO) to obtain the yellow solid product 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I199 (0.6 g, 64.6% yield).

[0470] The product was confirmed by LCMS.

[0471] Step 8 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2,3-Dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I199 (400 mg, 0.84 mmol) was dissolved in NH3 / MeOH (20 mL, 9 mol / L) in a microwave tube, and the mixture was stirred at 60 °C in a sealed container for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.HO) to give the white solid product 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T042 (15 mg, 3.87% yield).

[0472] The product was confirmed by LCMS, H-NMR and C-NMR.

[0473] 1 H NMR (400 MHz, CDCl3) δ: 11.67 (br s, 1H), 11.10 (s, 1H), 7.37 (s, 1H), 7.21 (d, 1H, J=6.4Hz), 6.92 (d, 1H, J=7.6Hz), 6.87 (s, 1H), 6.14 (br s, 1H), 5.38 (s, 2H), 4.61 (t, 2H, J=8.8Hz), 3.79 (s, 2H), 3.37-3.38 (m, 2H), 3.23 (t, 2H, J=8.8Hz), 3.12-3.14 (m, 2H), 2.86 (s, 2H), 2.08-2.18 (m, 4H), 1.98-2.01 (m, 2H), 1.70-1.72 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ: 180.13, 168.46, 164.94, 162.01, 160.36, 154.50, 136.71, 127.94, 125.39, 120.86, 109.30, 97.92, 71.53, 69.98, 55.61, 54.01, 29.33, 27.64, 25.98, 23.52. Example 24: Synthesis of Compound T044 The synthetic route is as follows: [ka] Step 1 5-(bromomethyl)-2,3-dihydrobenzofuran 5-(Bromomethyl)-2,3-dihydrobenzofuran 5-(Hydroxymethyl)-2,3-dihydrobenzofuran (1 g, 6.66 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. PBr3 (2.7 g, 9.99 mmol) was added and the reaction mixture was stirred at room temperature for approximately 1 h. After the reaction was complete, cold saturated aqueous sodium bicarbonate (20 mL x 2) was added to the mixture. After separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude white solid product 5-(bromomethyl)-2,3-dihydrobenzofuran I203 (1.2 g, 84.6% yield).

[0474] The product was confirmed by LCMS.

[0475] Step 2 methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (0.5 g, 2.11 mmol) and potassium carbonate (0.58 g, 4.21 mmol) were dissolved in DMF (5 mL), and 5-(bromomethyl)-2,3-dihydrobenzofuran I203 (494 mg, 2.32 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (20 mLx3). The organic phase was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA=10 / 1) to give the white solid product 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I204 (0.5 g, 64.2% yield).

[0476] The product was confirmed by LCMS and H-NMR.

[0477] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.32 (s,1H), 7.23 (d,1H, J=7.6Hz), 6.79 (d,1H, J=8.0Hz), 5.41 (s, 2H), 4.58-4.63 (m, 2H), 3.95 (s, 3H), 3.47 (s, 3H), 3.22-3.26 (m,2H). Step 3 methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I204 (0.2 g, 0.54 mmol) was dissolved in THF (5 mL), and 2,4-dimethoxybenzylamine (453 mg, 2.71 mmol) was added. The reaction mixture was stirred at 60 °C for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water (10 mL), adjusted to pH 5, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the white solid product, 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I205 (0.19 g, 76.9% yield).

[0478] The product was confirmed by LCMS.

[0479] Step 4 methyl 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I205 (683 mg, 1.50 mmol) was dissolved in DCM / HO (5 / 1 mL), and DDQ (509 mg, 2.24 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After the reaction was completed, the mixture was filtered, the filtrate was added to water (10 mL) and extracted with DCM (20 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by chromatography column (PE / EA=10 / 1~3 / 1) to give the yellow solid product 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I206 (0.1 g, 21.8% yield).

[0480] The product was confirmed by LCMS.

[0481] Step 5 methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (65 mg, 0.46 mmol) was dissolved in anhydrous THF (2 mL) and cooled to 0 °C under nitrogen gas protection. CDI (74 mg, 0.46 mmol) was added and the mixture was stirred for 30 minutes and then stirred at room temperature for another 1 hour. DMSO (2 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I206 (0.1 g, 0.33 mmol) and potassium carbonate (90 mg, 0.65 mmol) were added and the mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude yellow oily liquid product 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I207 (0.1 g, 64.6% yield).

[0482] The product was confirmed by LCMS.

[0483] Step 6 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((2,3-Dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I207 (0.25 g, 0.53 mmol) was dissolved in NH3 / MeOH (6 mL, 9 mol / L) in a microwave tube, and the mixture was stirred at 65 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.HO) to give the white solid product, 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T044 (18 mg, 7.44% yield).

[0484] The product was confirmed by LCMS, H-NMR and C-NMR.

[0485] 1 H NMR (400MHz, CDCl3): δ (ppm) 11.07 (s,1 H), 7.44-7.47 (m, 1H), 7.28-7.30 (m, 1H), 7.16-7.22 (m, 2H), 6.80 (d,1H, J=8.4Hz), 3.59 (s, 1H), 3.37 (s, 2H), 4.59-4.63 (m, 2H), 3.26-3.37 (m, 2H), 3.06-3.26 (m, 2H), 2.93-2.99 (m, 4H), 2.86-2.92 (m, 2H), 2.03-2.35 (m, 4H), 1.86-2.00 (m, 2H), 1.65-1.86 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ: 169.34, 165.76, 162.15, 160.53, 154.25, 129.15, 127.89, 127.60, 125.84, 109.34, 97.49, 71.50, 71.42, 70.63, 55.46, 53.85, 39.80, 39.74, 29.58, 29.49, 27.40, 25.02, 23.37 Example 25: Synthesis of Compound T045 The synthetic route is as follows: [ka] Step 1 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine 3-Bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine 5-Bromopyridin-3-ol (1.5 g, 8.62 mmol) was dissolved in DMF (15.0 mL), and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.76 g, 10.35 mmol) and sodium hydroxide (1.38 g, 34.48 mmol) were added. The reaction mixture was heated to 70 °C and stirred for 2 hours. The reaction mixture was poured into water (60 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine I208 (1.6 g, 68.5% yield) as a yellow oil.

[0486] The product was confirmed by LCMS.

[0487] Step 2 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine 3-Bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine I208 (1 g, 3.69 mmol) was dissolved in NMP (10 mL) and CuO (594 mg, 7.38 mmol) and NH₃·H₂O (10 mL) were added at room temperature. The mixture was stirred at 120 °C for 16 h. After completion of the reaction, the insoluble material was filtered through diatomaceous earth. The filtrate was extracted with dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (DCM / MeOH = 120 / 1-40 / 1, 0.1% NH₃·H₂O) to give 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine I209 (0.6 g, 78.5% yield) as a yellow solid.

[0488] The product was confirmed by LCMS.

[0489] Step 3 methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylate 3-((4-Bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylic acid methyl ester 3-[(4-Bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid methyl ester I178 (0.9 g, 2.04 mmol) was dissolved in THF (30 mL), and LiHMDS (1 M, 4.50 mL) and 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine I209 (464 mg, 2.24 mmol) were added at room temperature. The mixture was stirred at 30°C for 5 hours. After the reaction was completed, the mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (DCM / MeOH=150 / 1-120 / 1) to obtain yellow oily liquid product 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylic acid methyl ester I210 (0.27 g, 23.3% yield).

[0490] The product was confirmed by LCMS.

[0491] Step 4 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide In a microwave tube, 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylic acid methyl ester I210 (0.36 g, 0.63 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L), and the mixture was reacted at 65 °C for 16 hours with stirring in a sealed container. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1, 1% NH3.HO) to give the white solid product 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide T045 (30 mg, 8.56% yield).

[0492] The product was confirmed by LCMS, H-NMR and C-NMR.

[0493] 1 H NMR (400 MHz, DMSO-d6) δ: 11.17 (s, 1H), 8.08-8.13 (m, 2H), 7.69 (s, 1H), 7.57-7.59 (d, 2H, J=8.0 Hz), 7.28-7.29 (m, 1H), 6.85 (s, 1H), 5.51 (s, 2H). 4.19 (t, 2H, J=5.6Hz), 2.85 (s, 2H), 2.57 (m, 4H), 1.70 (s, 4H). 13 C NMR (100 MHz, CDCl3+CD3OD) δ: 172.32, 166.01, 162.87, 162.80, 160.35, 160.26, 155.27, 137.15, 132.64, 132.04, 123.56, 115.87, 115.65, 115.58, 111.02, 110.91, 110.84, 96.47, 66.41, 58.01, 54.62, 54.35, 29.62, 23.24. Example 26: Synthesis of Compound T046 The synthetic route is as follows: [ka] Step 1 tert-butyl 4-(2-(4-nitro-1H-pyrazol-1-yl) ethyl) piperazine-1-carboxylate 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester 4-(2-Hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (3 g, 13.0 mmol) was dissolved in THF (30 mL) and 4-nitro-1H-pyrazole (1.6 g, 14.3 mmol), DIAD (4 g, 19.5 mmol), and PPh3 (5.1 g, 19.5 mmol) were added at room temperature and allowed to react for 2 h with stirring. After the reaction was complete, the mixture was added to water (100 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude yellow solid product, 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester I211 (5 g, crude), which was used directly in the next reaction.

[0494] The product was confirmed by LCMS.

[0495] Step 2 tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl) ethyl) piperazine-1-carboxylate 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester 4-(2-(4-Nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester I211 (5 g, crude) and Pd / C (0.5 g) were dissolved in anhydrous MeOH (100 mL) and reacted at room temperature under 50 psi hydrogen gas with stirring for 2 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude red solid product 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester I212 (2.5 g, 55% yield).

[0496] The product was confirmed by LCMS and H-NMR.

[0497] 1 H NMR (400 MHz, CDCl3) δ: 7.17 (s, 1H), 7.10 (s, 1H), 4.14 (t, 2H, J=6.4Hz), 3.43 (t, 4H, J=4.8Hz), 2.79 (t, 1H, J=6.4Hz), 2.42 (s, 4H), 1.47 (s, 9H). Step 3 methyl 3-((4-bromo-2,6-difluorobenzyl) oxy)-5-((1-(2-(4-(tert-butoxycarbonyl) piperazin-1-yl) ethyl)-1H-pyrazol-4-yl) amino) isothiazole-4-carboxylate 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxylic acid methyl ester 3-[(4-Bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylic acid methyl ester I178 (300 mg, 0.68 mmol) and 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester I212 (240 mg, 0.30 mmol) were dissolved in anhydrous THF (30 mL), and LiHMDS (1 M, 1.4 mL, 1.36 mmol) was added at room temperature. The mixture was stirred for approximately 1 hour. After complete reaction, water (30 mL) was added to the mixture and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography to give the white solid product 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxylic acid methyl ester I213 (10 mg, 2.2% yield).

[0498] The product was confirmed by LCMS and H-NMR.

[0499] 1 H NMR (400 MHz, CDCl3) δ: 9.32 (s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 7.16 (d, 2H, J=6.8Hz), 5.45 (s, 2H), 4.25 (t, 2H, J=6.4Hz), 3.81 (s, 3H), 3.44-3.45 (m, 4H), 2.83 (t, 2H, J=6.0Hz), 2.45 (s, 4H), 1.48 (s, 9H). Step 4 tert-butyl 4-(2-(4-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino) -1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate 4-(2-(4-((3-((4-bromo-2,6-difluorophenyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester In a microwave tube, 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butyloxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxylic acid methyl ester I213 (160 mg, 0.24 mmol) was dissolved in NH3 / MeOH (5 mL, 9 mol / L) and the mixture was reacted at 70 °C for 48 h with stirring in a sealed container. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1, 1% NH3.HO) to give the white solid product 4-(2-(4-((3-((4-bromo-2,6-difluorophenyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester T046 (7 mg, 4.4% yield).

[0500] The product was confirmed by LCMS and H-NMR.

[0501] 1H NMR (400 MHz, CDCl3) δ: 10.09 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.19 (d, 2H, J=6.8Hz), 6.83 (s, 1H), 5.54 (s, 2H), 5.34 (s, 1H), 4.53 (s, 2H), 3.62 (s, 4H), 2.54-2.66 (m, 4H), 1.63-1.68 (m, 2H), 1.47 (s, 9H). Example 27: Synthesis of Compound T049 The synthetic route is as follows: [ka] Step 1 N,3-dimethylbenzamide N,3-dimethylbenzamide N,3-Dimethylbenzoic acid (5 g, 36.72 mmol) was dissolved in anhydrous DMF (50 mL) and methylamine·HCl (2.73 g, 40.40 mmol), DIEA (23.73 g, 183.62 mmol), EDCI (8.45 g, 44.07 mmol), and HOBt (5.95 g, 44.07 mmol) were added at room temperature. The mixture was stirred for 3 hours. After the reaction was complete, the mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, N,3-dimethylbenzamide I218 (4.8 g, 87.6% yield). This crude product was purified by flash column chromatography (PE / EA = 3 / 1-1 / 1) to give a yellow oily liquid.

[0502] The product was confirmed by LCMS and H-NMR.

[0503] 1H NMR (400 MHz, CDCl3) δ: 7.61 (s, 1H), 7.49-7.57 (m, 1H), 7.31-7.34 (m, 2H), 6.23 (s, 1H), 3.03 (d, 3H, J=4.4Hz), 2.41 (s, 3H). Step 2 3-(bromomethyl)-N-methylbenzamide 3-(Bromomethyl)-N-methylbenzamide N,3-Dimethylbenzamide I218 (4 g, 26.81 mmol) was dissolved in CCl4 (80 mL), and AIBN (440 mg, 2.68 mmol) and NBS (5.73 g, 32.17 mmol) were added at room temperature. The mixture was heated to 80 °C in an oil bath and refluxed with stirring for 16 h. After the reaction was complete, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography (PE / EA = 10 / 1-5 / 1-1 / 1) to give the brown oily liquid product, 3-(bromomethyl)-N-methylbenzamide I219 (4.6 g, crude).

[0504] Step 3 methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (2 g, 8.43 mmol) and potassium carbonate (3.5 g, 25.29 mmol) were dissolved in DMF (40 mL), and 3-(bromomethyl)-N-methylbenzamide I219 (4.61 g, 10.12 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. Water (200 mL) was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate (50 mLx3). The organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA=5 / 1-3 / 1-1 / 1-1 / 2) to give the white solid product 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I220 (2.4 g, 74.06% yield).

[0505] The product was confirmed by LCMS and H-NMR.

[0506] 1 H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.72 (d, 1H, J=7.6Hz), 7.60 (d, 1H, J=8.0Hz), 7.47 (t, 1H, J=8.0Hz), 6.23 (s, 1H), 5.54 (s, 2H), 4.00 (s, 3H), 3.50 (s, 3H), 3.05 (d, 3H, J = 5.2Hz). Step 4 methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I220 (2 g, 5.2 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (8.7 g, 52.03 mmol) was added. The reaction mixture was stirred at 65 °C for 1 hour. After completion of the reaction, the reaction solution was added to water (100 mL), and the mixture was filtered to obtain a filter cake. The filter cake was washed with water and then dried to give the white solid product, 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester I221 (2.2 g, 89.7% yield).

[0507] The product was confirmed by LCMS and H-NMR.

[0508] 1 H NMR (400 MHz, CDCl3) δ: 8.13 (t, 1H, J=5.6Hz), 7.91 (s, 1H), 7.71 (d, 1H, J=7.6Hz), 7.59 (d, 1H, J=8.0Hz), 7.44 (t, 1H, J=7.6Hz), 7.18 (d, 1H, J=8.4Hz), 6.39-6.50 (m, 2H), 6.21 (s, 1H), 5.46 (s, 2H), 4.29 (d, 2H, J=6.0Hz), 3.87 (s, 6H), 3.82 (s, 3H), 3.04 (d, 2H, J=4.8Hz). Step 5 methyl 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate 5-Amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester 5-((2,4-Dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester I221 (2 g, 4.24 mmol) was dissolved in DCM / HO (150 / 30 mL). DDQ (3.85 g, 16.97 mmol) was added portionwise at 0 °C. The reaction mixture was stirred at room temperature for 5 min. After the reaction was complete, neutral aluminum oxide was added to the mixture, which was then concentrated under reduced pressure. The liquid was purified by chromatography (neutral aluminum oxide, PE / EA = 100 / 1, 50 / 1, 20 / 1) to give the pale yellow solid product, 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester I222 (1 g, 73.37% yield).

[0509] The product was confirmed by LCMS.

[0510] Step 6 methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (177 mg, 1.24 mmol) was dissolved in anhydrous THF (4 mL) and cooled to 0 °C under nitrogen gas protection. CDI (179 mg, 1.24 mmol) was added and the mixture was stirred for 30 minutes and then stirred at room temperature for 1 hour. DMSO (4 mL) was added and most of the THF was removed under reduced pressure. 5-Amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester I222 (400 mg, 1.24 mmol) and potassium carbonate (344 mg, 2.49 mmol) were added and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I223, which was directly used in the next reaction.

[0511] The product was confirmed by LCMS and H-NMR.

[0512] 1 H NMR (400 MHz, CDCl3) δ: 10.23 (br s, 1H), 8.10 (br s, 1H), 7.94 (s, 1H), 7.70 (d, 1H, J=5.6Hz), 7.59 (d, 1H, J=7.6Hz), 7.44 (t, 1H, J=7.6Hz), 6.30 (s, 1H), 5.47 (s, 2H), 3.90 (s, 3H), 3.31 (s, 2H), 3.04 (d, 3H, J=4.8Hz), 2.59 (s, 4H), 2.52 (t, 2H, J=6.0Hz), 1.86-1.88 (m, 4H), 1.66-1.68 (m, 4H). Step 7 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I223 (150 mg, 0.31 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L) in a microwave tube, and the mixture was stirred at 65 °C in a sealed container for 24 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by preparative high-performance chromatography to give the white solid product, 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T049 (25.7 mg, 17.7% yield).

[0513] The product was confirmed by LCMS, H-NMR and C-NMR.

[0514] 1 H NMR (400 MHz, CDCl3) δ: 10.92 (br s, 1H), 7.88 (s, 2H), 7.76 (d, 1H, J=7.6Hz), 7.59 (d, 1H, J=7.2Hz), 7.48 (t, 1H, J=8.0Hz), 7.12 (s, 2H), 6.22 (s, 1H), 5.52 (s, 2H), 5.48 (s, 1H), 3.33 (s, 3H), 3.05 (d, 3H, J=4.8Hz), 2.59 (s, 4H), 2.48-2.56 (m, 2H), 1.88 (s, 4H), 1.71-1.69 (m, 4H). 13C NMR (100 MHz, CDCl3+ CD3OD) δ: 173.17, 172.60, 169.79, 165.76, 158.43, 140.24, 138.82, 135.08, 132.85, 131.04, 130.83, 73.83, 59.91, 57.88, 43.82, 31.52, 30.45, 29.70, 27.07. Example 28: Synthesis of Compound T050 The synthetic route is as follows: [ka] Step 1 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino) isothiazole-4-carboxamide 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxamide 4-(2-(4-((3-((4-bromo-2,6-difluorophenyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester T046 (50 mg, 0.078 mmol) was dissolved in HCl / MeOH (5 mL, 8 mol / L) at room temperature and reacted with stirring for 2 hours. After the reaction was completed, the mixture was directly concentrated under reduced pressure, water was added to the residue, and the pH was adjusted to 9 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give the white solid product 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxamide T050 (18.8 mg, 44.5% yield).

[0515] The product was confirmed by LCMS, H-NMR and C-NMR.

[0516] 1 H NMR (400 MHz, CDCl3) δ: 10.04 (s, 1H), 7.60 (s, 1H), 7.49 (s, 1H), 7.18-7.25 (m, 2H), 6.82 (s, 1H), 5.54 (s, 2H), 5.32 (s, 1H), 4.24 (t, 2H, J=6.0Hz), 2.92-2.95 (m, 4H), 2.80-2.83 (m, 2H), 2.37-2.50 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 176.72, 166.01, 162.96, 162.91, 162.89, 160.43, 160.35, 133.93, 132.55, 123.55, 123.42, 123.30, 123.05, 122.46, 115.91, 115.88, 115.82, 115.69, 115.64, 115.61, 115.54, 111.36, 111.16, 94.28, 58.18, 57.68, 57.64, 57.61, 54.27, 54.20, 54.17, 50.26, 46.00,45.93. Example 29: Synthesis of Compound T051 The synthetic route is as follows: [ka] Step 1 ethyl 5,6-dichloronicotinate Ethyl 5,6-dichloronicotinate 5,6-Dichloronicotinic acid (15 g, 78 mmol) and thionyl chloride (27.6 g, 234 mmol) were dissolved in ethanol (150 mL) and the reaction mixture was stirred at 60 °C for 1.0 h. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid crude product, ethyl 5,6-dichloronicotinate I224 (15 g, 87% yield).

[0517] The product was confirmed by LCMS and H-NMR.

[0518] 1 H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 1.6 Hz, 1H), 4.44 (dd, J = 21.6, 7.0 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). Step 2 ethyl 5-chloro-6-cyanonicotinate: 5-Chloro-6-cyanonicotinic acid ethyl ester Ethyl 5,6-dichloronicotinate I224 (8 g, 36 mmol), zinc cyanide (3.16 mg, 27 mmol), and tetrakis(triphenylphosphine)palladium (4.15 g, 3.6 mmol) were dissolved in DMF (80 mL). The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 50:1 to 30:1) to give the white solid product, 5-chloro-6-cyanonicotinic acid ethyl ester I225 (3 g, 38.7% yield).

[0519] The product was confirmed by LCMS and H-NMR.

[0520] 1 H NMR (400 MHz, CDCl3) δ 9.17 (d, J = 1.6 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). Step 3 ethyl 6-(aminomethyl)-5-chloronicotinate: 6-(Aminomethyl)-5-chloronicotinic acid ethyl ester 5-Chloro-6-cyanonicotinic acid ethyl ester I225 (8.8 g, 41.78 mmol) was dissolved in acetic acid (100 mL), Raney nickel (2.45 g, 41.78 mmol) was added, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a green solid crude product, 6-(aminomethyl)-5-chloronicotinic acid ethyl ester I226 (4.40 g, 58.4% yield).

[0521] The product was confirmed by LCMS and H-NMR.

[0522] 1 H NMR (400 MHz, D2O) δ 8.74 (s, 1H), 8.13 (s, 1H), 4.27 (s, 3H), 4.13 (s, 2H), 1.10 (s, 3H). Step 4 ethyl 5-chloro-6-(formamidomethyl)nicotinate: 5-Chloro-6-(formamidomethyl)nicotinic acid ethyl ester 6-(Aminomethyl)-5-chloronicotinic acid ethyl ester I226 (8.8 g, 41.00 mmol) was dissolved in acetic anhydride (20 mL) and formic acid (100 mL), and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid crude product, 5-chloro-6-(formamidomethyl)nicotinic acid ethyl ester I227 (6 g, 60.3% yield).

[0523] The product was confirmed by LCMS.

[0524] Step 5 ethyl 8-chloroimidazo[1,5-a]pyridine-6-carboxylate 8-Chloroimidazo[1,5-a]pyridine-6-carboxylic acid ethyl ester 5-Chloro-6-(formamidomethyl)nicotinic acid ethyl ester I227 (6 g, 24.73 mmol) was dissolved in toluene (50 mL), phosphorus oxychloride (15.17 g, 98.90 mmol) was added, and the reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1:1) to give the yellow solid product, 8-chloroimidazo[1,5-a]pyridine-6-carboxylic acid ethyl ester I228 (2.5 g, 45.0% yield).

[0525] The product was confirmed by LCMS and H-NMR.

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.69 (s, 1H), 7.54 (s, 1H), 7.22 (d, J = 0.4 Hz, 1H), 4.34 (d, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H). Step 6 (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol 8-Chloroimidazo[1,5-a]pyridine-6-carboxylic acid ethyl ester I228 (2 g, 8.90 mmol) was dissolved in THF (20 mL) and DIBAL-H (7.2 mL, 35.61 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2.0 h. The reaction mixture was quenched with water (15 mL), filtered through diatomaceous earth, washed with ethyl acetate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10:1 to 2:1) to give the yellow solid product (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol I229 (360 mg, 22.14% yield).

[0527] The product was confirmed by LCMS and H-NMR.

[0528] 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.27 (s, 1H), 7.42 (s, 1H), 6.93 (s, 1H), 5.42 (t, J = 5.6 Hz, 1H), 4.42-4.44 (m, 2H). Step 7 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine 6-(Bromomethyl)-8-chloroimidazo[1,5-a]pyridine (8-Chloroimidazo[1,5-a]pyridin-6-yl)methanol I229 (270 mg, 1.48 mmol) was dissolved in DCM (20 mL), PBr (400 mg, 1.48 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give crude yellow solid 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine I230 (330 mg, 90.9% yield).

[0529] The product was confirmed by LCMS.

[0530] Step 8 methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester 3-Hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I009 (319 mg, 1.34 mmol) was dissolved in DMF (5 mL), and 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine I230 (330 mg, 1.34 mmol) and potassium carbonate (557 mg, 4.03 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin layer chromatography (PE / EA=1:1) to give a yellow solid product, 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I231 (120 mg, 22.2% yield).

[0531] The product was confirmed by LCMS and H-NMR.

[0532] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.57 (s, 1H), 8.53 (s, 1H), 7.49 (s, 1H), 7.11 (s, 1H), 5.44 (s, 1H), 3.89 (s, 1H), 3.62 (s, 1H). Step 9 methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino) isothiazole-4-carboxylate 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester 3-((8-Chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I231 (120 mg, 0.30 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (50 mg, 0.30 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by high performance liquid chromatography to give a yellow solid product, 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I232 (60 mg, 41.1% yield).

[0533] The product was confirmed by LCMS and H-NMR.

[0534] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.42 (s, 1H), 7.46 (s, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.05 (s, 1H), 6.60 (s, 1H), 6.51 (d, J = 7.7 Hz, 1H), 5.27 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 6H). Step 10 methyl 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylate 5-Amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester I232 (50 mg, 0.10 mmol) was dissolved in DCM (5 mL) and water (1 mL), and DDQ (93 mg, 0.41 mmol) was added in portions at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA=1 / 1) to give the yellow solid product, 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I233 (13.5 mg, 38.9% yield).

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

[0536] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.56 (s, 1H), 8.43 (s, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 5.27 (s, 2H), 3.73 (s, 3H). Step 11 methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 4-(Pyrrolidin-1-yl)butan-1-amine (12 mg, 83 μmol) was dissolved in anhydrous THF (2 mL). CDI (13 mg, 83 μmol) was added under nitrogen gas protection. The mixture was stirred at room temperature for 2.0 hours. DMSO (2 mL) was added, and the THF was removed under reduced pressure. 5-Amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I233 (20 mg, 59 μmol) and potassium carbonate (16 mg, 118 μmol) were added, and the mixture was stirred at room temperature for 2.0 hours. The reaction mixture was poured into water (8 mL), and the mixture was separated and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative thin layer chromatography (DCM / MeOH= 10 / 1) to giv...

Claims

1. The compound has the following structure: 【Chemistry 1】 (I) where: Ring A is a 5-7 membered heteroaryl ring; The B ring is C 6 -C 10 an aryl ring or a 5- to 10-membered heterocyclic ring, 6 -C 10 The aryl ring or the 5- to 10-membered heterocyclic ring is optionally C 6 -C 10 Aryl ring, C 5 -C 8 may be condensed with an aliphatic ring or a 5- to 10-membered heterocycle; X 1 is O or S, Y is -N(C 0 -C 10 alkyl group)(C 0 -C 10 alkyl group) or -O(C 0 -C 10 alkyl group), L 1 represents a single bond, -C(O)-, -C(O)O-, -C(O)NR 3 -, -C(O)N(R 3 )O-, -S(O) 2 -, -S(O) 2 NR 3 -, -S(O)-, -S(O)NR 3 - and -Cy-, where -Cy- is selected from a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, and a substituted or unsubstituted heterocyclylene group; L 2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently 【Chemistry 2】 , -N(R 4 )-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -N(R 4 )S(O) 2 -, -S(O) 2 N(R 4 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 where a and b are independently selected from integers 0 to 10, and R L201 and R L202 are independently H, C 1 -C 10 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR L203 , -C(O)R L203 , -C(O)OR L203 , -NR L204 C(O)OR L203 , -OC(O)R L203 , -NR L204 SO 2 R L203 , -SO 2 NR L203 R L204 , -NR L204 C(O)R L203 , -C(O)NR L203 R L204 , -NR L203 R L204 , -SR L203 , -S(O)R L203 , -S(O) 2 R L203 , -SO 3 H, C 3 -C 6 selected from cycloalkyl groups, cycloalkylalkyl groups, heterocyclyl groups, and heterocyclylalkyl groups, where R L203 and R L204 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; L 3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently 【Transformation 3】 , -N(R 5 )-, -N(R 5 )C(O)-, -C(O)N(R 5 )-, -N(R 5 )S(O) 2 -, -S(O) 2 N(R 5 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 wherein c and d are each independently selected from an integer of 0 to 10; L301 and R L302 are independently H, C 1 -C 10 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR L303 , -C(O)R L303 , -C(O)OR L303 , -NR L304 C(O)OR L303 , -OC(O)R L303 , -NR L304 SO 2 R L303 , -SO 2 NR L303 R L304 , -NR L304 C(O)R L303 , -C(O)NR L303 R L304 , -NR L303 R L304 , -SR L303 , -S(O)R L303 , -S(O) 2 R L303 , -SO 3 H, C 3 -C 6 selected from cycloalkyl groups, cycloalkylalkyl groups, heterocyclyl groups, and heterocyclylalkyl groups, where R L303 and R L304 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group; Each R 3 ~R 5 are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group, wherein said alkyl group, cycloalkyl group, and heterocyclyl group are optionally substituted with halogen, cyano group, nitro group, azido group, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 1 -C 10 Silanyl group, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; R 1 are one or more independent substituents on the B ring, and each R 1 are independently H, C 1 -C 10 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NR 102 C(O)OR 101 , -OC(O)R 101 , -NR 102 SO 2 R 101 , -SO 2 NR 101 R 102 , -NR 102 C(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -S(O) j R 101 (where j is an integer from 0 to 2), -SO 3 H, -NR 102 (CR 103 R 104 ) t OR 101 , -(CH 2 ) t (C 6 -C 10 aryl group), -SO 2 (CH 2 ) t (C 6 -C 10 aryl group), -S(CH 2 ) t (C 6 -C 10 aryl group), -O(CH 2 ) t (C 6 -C 10 aryl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -SO 2 (CH 2 ) t (4-10 membered heterocyclyl group), -S(CH 2 ) t (4-10 membered heterocyclyl group), -O(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl group), -SO 2 (CH 2 ) t (C 3 -C 10 cycloalkyl group), -S(CH 2 ) t (C 3 -C 10 cycloalkyl group), -O(CH 2 ) t (C 3 -C 10 cycloalkyl groups), where t is an integer from 0 to 5, 1 -C 10 Alkyl group, C 6 -C 10 The aryl group and the 4- to 10-membered heterocyclyl group may optionally be substituted with a halogen atom, a cyano group, a nitro group, an azide group, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 1 -C 10 Silanyl group, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; Each R 101 ~R 104 are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, C 1 -C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR'', and -NR'SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 1 -C 10 Silanyl group, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valences permit); R 0 , : H, C 1 -C 10 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 001 , -C(O)R 001 , -C(O)OR 001 , -NR 002 C(O)OR 001 , -OC(O)R 001 , -NR 002 SO 2 R 001 , -SO 2 NR 001 R 002 , -NR 002 C(O)R 001 , -C(O)NR 001 R 002 , -NR 001 R 002 , -S(O) i R 002 (wherein i is an integer from 0 to 2), -SO 3 H, -NR 002 (CR 003 R 004 ) t OR 001 , 【Chemistry 4】 Selected from Here, the E ring is C 6 -C 10 an aryl ring or a 4- to 10-membered heterocyclic ring, 6 -C 10 The aryl ring or 4-10 membered heterocycle is optionally C 6 -C 10 Aryl ring, C 5 -C 8 may be condensed with an aliphatic ring or a 4- to 10-membered heterocycle; R 2 H, =O, C 1 -C 10 Alkyl group, C 2 -C 10 Alkenyl group, C 2 -C 10 Alkynyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, -OR 201 , -C(O)R 201 , -C(O)OR 201 , -NR 202 C(O)OR 201 , -OC(O)R 201 , -NR 202 SO 2 R 201 , -SO 2 NR 201 R 202 , -NR 202 C(O)R 201 , -C(O)NR 201 R 202 , -NR 201 R 202 , -S(O) i R 201 (wherein i is an integer from 0 to 2), -SO 3 H, -(CH 2 ) j (C 6 -C 10 aryl group), -SO 2 (CH 2 ) j (C 6 -C 10 aryl group), -S(CH 2 ) j (C 6 -C 10 aryl group), -O(CH 2 ) j (C 6 -C 10 aryl group), -(CH 2 ) j (4-10 membered heterocyclyl group), -SO 2 (CH 2 ) j (4-10 membered heterocyclyl group), -S(CH 2 ) j (4-10 membered heterocyclyl group), -O(CH 2 ) j (4-10 membered heterocyclyl group), -(CH 2 ) j (C 3 -C 10 cycloalkyl group), -SO 2 (CH 2 ) j (C 3 -C 10 cycloalkyl group), -S(CH 2 ) j (C 3 -C 10 cycloalkyl group), -O(CH 2 ) j (C 3 -C 10 cycloalkyl groups), where j is an integer from 0 to 5, 1 -C 10 Alkyl group, C 6 -C 10 The aryl group and the 4- to 10-membered heterocyclyl group may optionally be substituted with a halogen atom, a cyano group, a nitro group, an azide group, —OR′, —C(O)R′, —C(O)OR′, —OC(O)R′, —NR′C(O)OR″, —NR′SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valences permit); Each R 001 ~R 004 are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, C 1 -C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR'', and -NR'SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 1 -C 10 Silanyl group, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; Each R 201 ~R 204 are each independently H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted heterocyclylalkyl group, C 1 -C 10 silanyl groups, wherein the alkyl, cycloalkyl, and heterocyclyl groups are optionally selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR'', and -NR'SO 2 R'', -SO 2 NR'R'', -NR'C(O)R'', -C(O)NR'R'', -NR'R'', -SR', -SOR', -SO 2 R', -SO 3 H, C 1 -C 10 Alkyl group, C 1 -C 10 Halogenated alkyl groups, C 1 -C 10 Silanyl group, C 3 -C 10 substituted by a group selected from a cycloalkyl group, a phenyl group, and a 4- to 10-membered heterocyclyl group; R' and R'' are each independently selected from H, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkylalkyl group, a substituted or unsubstituted heterocyclyl group, and a substituted or unsubstituted heterocyclylalkyl group, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof. 【Request Item 2】 【Chemistry 5】

3. Ring B is a benzene ring, a benzoaliphatic ring, or a heterocyclic ring; 【Transformation 6】 【Transformation 7】 The compound according to claim 1 or 2, characterized in that it is selected from any one of the structures:

4. Each R 1 are each independently 1 -C 6 Alkyl groups, halogens, C 1 -C 6 Halogenated alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO 2 R 101 , -SO 2 NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O) 2 R 101 , -SO 3 H, -(CH 2 ) t (phenyl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl groups), where t is an integer from 0 to 5; Preferably, R 101 and R 102 are independently H, C 1 -C 6 Alkyl group 【Transformation 8】 , C 1 -C 6 Halogenated alkyl groups (e.g., -CHF 2 , -CH 2 F, -CF 3 , -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 CH 2 -CF 3 , -CH 2 CH 2 CH 2 -CF 3 ), C 1 -C 6 Hydroxy-substituted alkyl groups (e.g., 【Chemistry 9】 Substituted or unsubstituted 4-10 membered heterocyclyl groups, such as 【Chemistry 10】 C 1 -C 10 Silanyl-substituted alkyl groups (e.g., 【Chemistry 11】 Selected from 【Chemistry 12】 The compound according to any one of claims 1 to 3, characterized in that it is selected from 【Request Item 5】 【Chemistry 13】

6. R 2 H, =O, C 1 -C 6 Alkyl group, C 1 -C 6 Halogenated alkyl groups, halogens, cyano groups, nitro groups, azide groups, -OR 201 , -C(O)R 201 , -C(O)OR 201 , -NHC(O)OR 201 , -OC(O)R 201 , -NHSO 2 R 201 , -SO 2 NR 201 R 202 , -NHC(O)R 201 , -C(O)NR 201 R 202 , -NR 201 R 202 , -SR 201 , -S(O) 2 R 201 , -SO 3 H, -(CH 2 ) j (phenyl group), -(CH 2 ) j (4-10 membered heterocyclyl group), -(CH 2 ) j (C 3 -C 10 cycloalkyl groups), where j is an integer from 0 to 5; Preferably, R 201 and R 202 are independently H, C 1 -C 6 Alkyl groups (e.g., -CH 3 , 【Chemistry 14】 ), C 1 -C 6 Halogenated alkyl groups (e.g., -CHF 2 , -CH 2 F, -CF 3 , -CH 2 -CH 2 F, -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 CH 2 -CF 3 , -CH 2 CH 2 CH 2 -CF 3 ), C 1 -C 6 Hydroxy-substituted alkyl groups (e.g., 【Chemistry 15】 ), C 1 -C 6 Alkoxy-substituted alkyl groups (e.g., 【Chemistry 16】 ), C 1 -C 6 Amino-substituted alkyl groups (e.g., 【Chemistry 17】 ), C 1 -C 6 Alkylamino-substituted alkyl groups (e.g., [Chemistry 18] ), C 3 -C 10 Cycloalkyl groups (e.g., 【Chemistry 19】 ), substituted or unsubstituted 4-10 membered heterocyclyl groups (e.g., 【Chemistry 20】 Selected from More preferably, R 2 is H, methyl group, ethyl group, n-propyl group, isopropyl group, -CF 3 , -CHF 2 , -CH 2 F, 【Chemistry 21】 , F, Cl, Br, I, cyano group, nitro group, azide group, hydroxy group, methoxy group, ethoxy group, 【Chemistry 22】 Selected from Even more preferably, R 0 Compounds according to any one of claims 1 to 5, characterized in that is selected from the following: 【Chemistry 23】

7. R 0 is -NR 001 R 002 where R 001 and R 002 are independently H, C 1 -C 6 Alkyl group, C 1 -C 6 Halogenated alkyl groups, C 1 -C 6 Hydroxy-substituted alkyl groups, C 1 -C 6 Alkoxy-substituted alkyl groups, C 1 -C 6 Amino-substituted alkyl groups, C 1 -C 6 Alkylamino-substituted alkyl group, C 3 -C 6 Cycloalkyl groups, C 4 -C 10 cycloalkylalkyl groups, Preferably, R 0 teeth, 【Chemistry 24】 Selected from, or R 0 is H, cyano group, -O(C 0 -C 10 alkyl group), -O(C 1 -C 10 silanyl group), -S(C 0 -C 10 alkyl group), -C(O)(C 0 -C 10 alkyl group), -C(O)O(C 0 -C 10 alkyl group), -OC(O)(C 0 -C 10 alkyl group), -N(C 0 -C 10 Alkyl group)SO 2 (C 0 -C 10 alkyl group), -SO 2 N(C 0 -C 10 alkyl group)(C 0 -C 10 alkyl group), -N(C 0 -C 10 alkyl group)C(O)(C 0 -C 10 alkyl group), -C(O)N(C 0 -C 10 alkyl group)(C 0 -C 10 alkyl group), -SO 2 (C 0 -C 10 alkyl group), wherein the alkyl group is optionally selected from halogen, cyano group, hydroxy group, amino group, C 1 -C 6 Alkoxy group, C 1 -C 6 Alkylamino group, C 3 -C 6 substituted by a group selected from cycloalkyl groups; Preferably, R 0 is H, cyano group, -OH, 【Chemistry 25】 The compound according to any one of claims 1 to 4, characterized in that it is selected from

8. L 1 is —C(O)NH—, —Cy-, a single bond or —C(O)—, Preferably, -Cy- is 【Chemistry 26】 Each R 10 are each independently H, halogen, or C 1 -C 6 Alkyl group, C 1 -C 6 Halogenated alkyl groups, C 1 -C 6 Alkoxy-substituted alkyl groups, C 1 -C 6 Alkylamino-substituted alkyl group, C 3 -C 6 Cycloalkyl groups, C 4 -C 10 cycloalkylalkyl groups, and 4- to 10-membered heterocyclyl groups; More preferably, -Cy- is 【Chemistry 27】 The compound according to any one of claims 1 to 7, characterized in that it is selected from:

9. L 2 is a single bond or C 2 -C 10 an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently selected from —N(R 4 )-, -N(R 4 )C(O)-, -C(O)N(R 4 )-, -N(R 4 )S(O) 2 -, -S(O) 2 N(R 4 )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) 2 wherein one or more H atoms in the alkylene group are optionally substituted independently by a group selected from H, C 1 -C 6 Alkyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, hydroxy group, C 1 -C 6 Alkoxy group, C 3 -C 6 Cycloalkyl groups, C 4 -C 10 substituted by a group selected from cycloalkylalkyl groups; Preferably, L 2 is C 2 -C 6 an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, and -S-; More preferably, L 2 is a single bond, 【Chemistry 28】 The compound according to any one of claims 1 to 8, characterized in that it is selected from

10. L 3 is C 1 -C 6 an alkylene group, wherein one or more methylene units in the alkylene group are optionally independently replaced by a group selected from -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, and wherein one or more H atoms in the alkylene group are optionally independently replaced by H, C 1 -C 6 Alkyl group, halogen, cyano group, nitro group, trifluoromethyl group, trifluoromethoxy group, azide group, hydroxy group, C 1 -C 6 Alkoxy group, C 3 -C 6 Cycloalkyl groups, C 4 -C 10 substituted by a group selected from cycloalkylalkyl groups; Preferably, L 3 The compound according to any one of claims 1 to 9, characterized in that is a methylene group.

11. The compound 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 【Transformation 33】 【Transformation 34】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 The compound according to claim 1, characterized in that it is selected from:

12. The stereoisomer is 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 The compound according to claim 1, characterized in that it is selected from:

13. L 1 is -C(O)NR 3 - or a single bond, 【Chemistry 41】 Part 【Chemistry 42】 where R 1 is C 1 -C 6 Halogenated alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO 2 R 101 , -SO 2 NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O) 2 R 101 , -SO 3 H, -(CH 2 ) t (phenyl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl group), where t is an integer from 0 to 5, preferably 【Chemistry 43】 The part is 【Chemistry 44】 where R 1b is C 1 -C 6 Halogenated alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO 2 R 101 , -SO 2 NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O) 2 R 101 , -SO 3 H, -(CH 2 ) t (phenyl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl groups), more preferably R 1b is C 1 -C 6 Halogenated alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101 , -(CH 2 ) t (4-8 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 6 cycloalkyl groups), where t is an integer from 0 to 5; R 1c are H, F, and C 1 -C 6 Alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO 2 R 101 , -SO 2 NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O) 2 R 101 , -SO 3 H, -(CH 2 ) t (phenyl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl groups), R 1a , R 1d , R 1e is H, C 1 -C 6 Alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), halogens (e.g., F, Cl, Br, I), C 1 -C 6 Halogenated alkyl group, cyano group, nitro group, azide group, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR 101 , -OC(O)R 101 , -NHSO 2 R 101 , -SO 2 NR 101 R 102 , -NHC(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -SR 101 , -S(O) 2 R 101 , -SO 3 H, -(CH 2 ) t (phenyl group), -(CH 2 ) t (4-10 membered heterocyclyl group), -(CH 2 ) t (C 3 -C 10 cycloalkyl groups), or L 1 is -C(O)NR 3 - and ring B is a monocyclic heterocycle, for example 【Chemistry 45】 Part 【Chemistry 46】 or L 1 The compound according to claim 1, characterized in that: is -Cy-.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, and one or more pharmaceutically acceptable excipients, Preferably, the pharmaceutical composition is an ophthalmic preparation such as eye drops, eye ointment, or the like.

15. 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, in the preparation of a medicament for the prevention and / or treatment of a hyperproliferative disease mediated by a protein tyrosine kinase.

16. the disease is a tumor, in particular a malignant tumor, preferably selected from breast cancer, lung cancer, adenocarcinoma, colorectal cancer, renal cancer, liver cancer, pancreatic adenocarcinoma, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, myeloid metaplasia of unknown cause, mesothelioma, myelodysplastic syndrome, hematopoietic malignancy, or The disease is an ocular disease, and is preferably diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema), age-related macular degeneration (including neovascular (exudative) age-related macular degeneration, non-exudative age-related macular degeneration, and geographic atrophy), pathological choroidal neovascularization (i.e., severe myopia, trauma, sickle cell anemia, ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve head drusen, and certain retinal dystrophies), pathological subretinal neovascularization (i.e., sickle cell anemia, ocular myopia, trauma ... and pathological subretinal neovascularization (i.e., sickle cell anemia, ocular myopia, trauma, and certain retinal dystrophies).

16. The use according to claim 15, characterized in that the cause is selected from the group consisting of erythrocytic retinopathy, Eales' disease, ocular ischemic syndrome, internal carotid artery cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic obliterative microarteritis, scattershot choroidoretinopathy, 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, Coats' disease, sickle cell retinopathy and / or neovascular glaucoma.

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