Protein tyrosine kinase inhibitor and ophthalmic preparation thereof

Abstract

The present invention relates to a protein tyrosine kinase inhibitor and an ophthalmic preparation thereof. The protein tyrosine kinase inhibitor not only effectively antagonizes the activity of a VEGFR receptor tyrosine kinase, but also improves the pharmacokinetic properties thereof, while exhibiting high selectivity in inhibiting the activity of an "off-target" EGFR tyrosine kinase, thereby reducing or avoiding side effects, particularly those affecting the eyes. The preparation can greatly improve the solubility of the protein tyrosine kinase inhibitor compound, prolong the residence time of the compound on the ocular surface, increase exposure in fundus tissue, and improve the bioavailability.

Description

A protein tyrosine kinase inhibitor and ophthalmic formulations thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a protein tyrosine kinase inhibitor and ophthalmic formulations thereof. BACKGROUND

[0002] Receptor tyrosine kinases play an important role in developmental biology, tissue homeostasis, and cancer biology. Receptor tyrosine kinases are composed 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, which results in an active conformation and subsequent activation of the intracellular signaling cascade. Due to their important influence on cells, tyrosine kinases are highly regulated. When these kinases are constitutively activated by mutation or overexpression and are independent of ligand, many diseases, such as cancer or ocular diseases such as diabetic retinopathy, develop through unregulated cell proliferation and other mechanisms. For this reason, tyrosine kinase inhibitors can be used to treat some diseases by interfering with this unregulated process. The development of inhibitors targeting pro-angiogenic receptor tyrosine kinases, mainly the vascular endothelial growth factor receptor (VEGFR) family (RTKi), has significantly improved the prognosis of some types of cancer, such as renal cell carcinoma, hepatocellular carcinoma, and colorectal cancer, and has become an effective treatment for tumor-related angiogenesis.

[0003] Diabetic retinopathy (DR) and age-related macular degeneration (AMD) are the leading causes of blindness worldwide. These pathologies are associated with neovascularization in the posterior segment of the eye, with DR preferentially presenting changes in neovascularization at the retinal level, while the hallmark of wet AMD is the formation of new blood vessels 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 receptors (VEGFRs) play a key role in these processes. Many proliferative disorders, such as ophthalmic diseases, tumors, and cancers, involve overexpression or upregulation of receptor tyrosine kinase (RTK) activity. Receptor tyrosine kinases are a class of kinase enzymes that modify proteins by chemically adding a phosphate group (phosphorylation). Phosphorylation often leads to functional changes in the target protein by altering enzyme activity, cellular localization, or binding to other proteins. Kinases are known to regulate most cellular pathways, especially those involved in signal transduction. To date, one of the approaches to inhibit the VEGF pathway is to inhibit receptor tyrosine kinase (RTK) activity. In the treatment of ocular diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), the goal of protein tyrosine kinase inhibitor therapy is to counteract pathological neovascularization and disease progression, preventing visual impairment. At the same time, the importance of VEGFR as a pro-angiogenic inducer in tumor growth, invasion, and extravasation makes it an excellent therapeutic target for a variety of cancers. However, existing VEGFR receptor tyrosine kinase inhibitors (RTKi) often also inhibit EGFR activity. This cross-reactivity can lead to adverse side effects by inhibiting biological functions associated with one or more of these off-target receptors. This problem greatly affects the application of VEGFR receptor tyrosine kinase inhibitors for the treatment of ophthalmic diseases. To date, the US FDA has not approved a small molecule tyrosine kinase inhibitor for the treatment of diabetic retinopathy and neovascular age-related macular degeneration.

[0004] The residence time of small molecule compounds on the ocular surface after conventional eye drop administration is very short. This is an important factor limiting the amount of compound that can be exposed to the fundus. The residence time on the ocular surface is also related to the viscosity of the formulation, and the literature (Patton.T.F.and Robinson, J.R. (1975) Ocular evaluation of polyvinyl alcohol vehicle in rabbits, J. Pharm. Sci. 64. 1312-1316.) shows that in rabbits, the ocular surface clearance rate is significantly reduced when the viscosity of the formulation reaches > 15 cps. This suggests to us that appropriately increasing the viscosity of eye drops is an important approach to optimizing the formulation. SUMMARY

[0005] The present application provides a compound for treating protein tyrosine kinase mediated proliferative diseases or conditions, such as ocular diseases with pathological neovascularization and malignant tumors, inhibiting VEGFR receptor tyrosine kinase activity while having selectivity for EGFR receptor tyrosine kinase inhibition to reduce side effects, especially adverse side effects on the eye.

[0006] To overcome the deficiencies of the prior art, the present application provides a protein tyrosine kinase inhibitor and an ophthalmic preparation thereof.

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

[0008] wherein,

[0009] A ring is a 5-7 membered heteroaromatic ring;

[0010] B ring is a C6-C 10 aromatic ring or 5-10 membered heterocyclic ring; optionally, the C6-C 10 aromatic ring or 5-10 membered heterocyclic ring can be fused with C6-C 10 aromatic ring, C5-C8 aliphatic ring, 5-10 membered heterocyclic ring;

[0011] X1 is O or S;

[0012] Y is -N(C0-C 10 alkyl)(C0-C 10 alkyl) or -O(C0-C 10 alkyl);

[0013] L1 is selected from: a single bond, -C(O)-, -C(O)O-, -C(O)NR3-, -C(O)N(R3)O-, -S(O)2-, -S(O)2NR3-, -S(O)-, -S(O)NR3-, -Cy-; -Cy- is selected from: substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heterocyclylene;

[0014] L2 is a single bond or alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted with 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; wherein a and b are independently selected from integers from 0 to 10, R L201 and R L202 are independently selected from: H, C1-C 10alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -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-C6cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, wherein R L203 and R L204 are independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl;

[0015] L3is alkylene, wherein one or more methylene units of the alkylene is optionally and independently substituted with a group selected from: -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 independently selected from an integer between 0 and 10, R L301 and R L302 are independently selected from the group consisting of H, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -OR L303 , -C(O)R L303 , -C(O)OR L303 , -NR L304 C(O)OR L303 , -OC(O)R L303 , -NR L304 SO2RL303 -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-C6cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, wherein R L303 and R L304 are independently selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl;

[0016] each R3to R5is independently selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, wherein the alkyl, cycloalkyl, heterocyclyl groups are optionally substituted with a group selected from: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 silyl, C3-C 10 cycloalkyl, phenyl, 4-10 membered heterocyclyl;

[0017] R1is one or more independent substituents on the B ring, each R1is independently selected from the group consisting of: H, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -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 R102 , -NR 102 C(O)R 101 , -C(O)NR 101 R 102 , -NR 101 R 102 , -S(O) j R 101 , -SO3H, -NR 102 (CR 103 R 104 ) t OR 101 , -(CH2) t (C6-C 10 aryl), -SO2(CH2) t (C6-C 10 aryl), -S(CH2) t (C6-C 10 aryl), -O(CH2) t (C6-C 10 aryl), -(CH2) t (4-10 membered heterocyclyl), -SO2(CH2) t (4-10 membered heterocyclyl), -S(CH2) t (4-10 membered heterocyclyl), -O(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl), -SO2(CH2) t (C3-C 10 cycloalkyl), -S(CH2) t (C3-C 10 cycloalkyl), -O(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; wherein said Ci-C 10 alkyl, C6-C 10 aryl, 4-10 membered heterocyclyl is optionally substituted with a group selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, Ci-C 10 alkyl, Ci-C 10 haloalkyl, Ci-C 10 silyl, C3-C 10 alkenyl, C3-CCycloalkyl, phenyl, 4-10 membered heterocyclic groups;

[0018] Each R 101 To R 104 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups;

[0019] m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if the valence allows);

[0020] R0 is selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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 Where i is an integer from 0 to 2, -SO3H, -NR 002 (CR 003 R 004 ) t OR 001 ,

[0021] wherein E is a C6-C 10 aromatic ring or 4-10 membered heterocyclic ring; optionally, the C6-C 10 aromatic ring or 4-10 membered heterocyclic ring can be fused to a C6-C 10 aromatic ring, C5-C8aliphatic ring, 4-10 membered heterocyclic ring;

[0022] R2is selected from the group consisting of: H, =O, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -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 wherein i is an integer from 0 to 2, -SO3H, -(CH2) j (C6-C 10 aryl), -SO2(CH2) j (C6-C 10 aryl), -S(CH2) j (C6-C 10 aryl), -O(CH2) j (C6-C 10 aryl), -(CH2) j (4-10 membered heterocyclyl), -SO2(CH2) j (4-10 membered heterocyclyl), -S(CH2) j (4-10 membered heterocyclyl), -O(CH2) j (4-10 membered heterocyclyl), -(CH2) j (C3-C 10 cycloalkyl), -SO2(CH2) j (C3-C 10 cycloalkyl), -S(CH2) j(C3-C 10 cycloalkyl), -0(CH2) j (C3-C 10 cycloalkyl), wherein j is an integer from 0 to 5; wherein said Ci-C 10 alkyl, C6-C 10 aryl, 4-10 membered heterocyclyl, is optionally substituted with a group selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 cycloalkyl, phenyl, 4-10 membered heterocyclyl;

[0023] n is an integer from 1-5 (e.g., 1, 2, 3, 4, 5, if valence allows);

[0024] each R 001 to R 004 is independently selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 silyl, wherein said alkyl, cycloalkyl, heterocyclyl is optionally substituted with a group selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 silyl, C3-C 10 cycloalkyl, phenyl, 4-10 membered heterocyclyl;

[0025] each R 201 to R 204 is independently selected from the group consisting of: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10silyl, wherein the alkyl, cycloalkyl, heterocyclyl are optionally substituted with a group selected from halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'SO2R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 alkyl, C1-C 10 haloalkyl, C1-C 10 silyl, C3-C 10 cycloalkyl, phenyl, 4-10 membered heterocyclyl;

[0026] R' and R" are independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl.

[0027] In some embodiments of the application, Y is -N(C0-C 10 alkyl)(C0-C 10 alkyl), such as -NH2, C1-C3 alkylamino.

[0028] In some embodiments of the application, Y is -O(C0-C 10 alkyl), such as -OH, C1-C3 alkoxy.

[0029] In particular, the A ring is a five- or six-membered aromatic or heteroaromatic ring, for example, the A ring is wherein Y1, Y2, Y3are independently selected from: O, S, N, C(R A ), R A selected from: H, halogen, substituted or unsubstituted alkyl, hydroxyl, alkoxy, amino, alkylamino, cyano, nitro; p is 0 or 1 ; in some embodiments of the application, the A ring is In particular

[0030] In one embodiment of the application, having the following structure:

[0031] In particular, R A selected from: H, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, amino, C1-C3 alkylamino, cyano, nitro; in some embodiments of the application R A is H.

[0032] In some embodiments of the application, Part has the following structure: In particular

[0033] Specifically, B ring is a benzene ring, a 5-6 membered monocyclic heterocycle, optionally, the benzene ring, 5-6 membered monocyclic heterocycle can be fused with a benzene ring, a C5-C8 aliphatic ring, a 5-6 membered, monocyclic heterocycle.

[0034] In some embodiments of the present application, B ring is a benzene ring, a benzo aliphatic ring, a heterocycle (including a monocyclic heterocycle (in particular, a 5-6 membered monocyclic heterocycle), a bicyclic heterocycle (in particular, a 9-11 membered bicyclic fused heterocycle)). In some embodiments of the present application, the 5-6 membered monocyclic heterocycle has the following structure: In some embodiments of the present application, the benzo aliphatic ring has the following structure: In some embodiments of the present application, the bicyclic heterocycle has the following structure:

[0035] Specifically, Part can have the following structure:

[0036] In some embodiments of the present application, B ring is a benzene ring, for example, Part is In other embodiments of the present application, B ring is a monocyclic heterocycle, in particular, a 5-6 membered monocyclic heterocycle, for example Part can be

[0037] In some embodiments of the present application, Part has the following structure: Wherein, R 1b is selected from: C1-C6 haloalkyl, cyano, nitro, azido, -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 , -SR101 -S(O)2R 101 -SO3H, -(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl); more particularly, R 1b is selected from the group consisting of: C1-C6 haloalkyl, cyano, nitro, azido, -OR 101 -C(O)R 101 -NHC(O)R 101 -C(O)NHR 101 -NHR 101 -SR 101 -(CH2) t (4-8 membered heterocyclyl), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5;

[0038] R 1c is selected from the group consisting of: H, F, C1-C6 alkyl, cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl);

[0039] R 1a , R 1d , R 1e is selected from the group consisting of: H, C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), halogen (e.g., F, Cl, Br, I), C1-C6 haloalkyl, cyano, nitro, azido, -OR 101 -C(O)R 101 -C(O)OR101 -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl);

[0040] each R 101 and R 102 is as defined above.

[0041] Further, R 1b may be selected from the group consisting of: -CF3, -CHF2, -CH2F, cyano, nitro, azido, -OH,

[0042] In some preferred embodiments of the present application, R 1b is -C(O)NR 101 R 102 wherein R 101 and R 102 are independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl.

[0043] Further, R 1a , R 1e may be independently selected from the group consisting of: H, halogen (such as F, Cl), C1-C3 alkyl (e.g. methyl).

[0044] Preferably, R 1c may be selected from the group consisting of: H, F.

[0045] Further, R 1d may be selected from the group consisting of: H, halogen (such as F, Cl), C1-C3 alkyl (e.g. methyl).

[0046] In some preferred embodiments of the present application, moieties have the following structure:

[0047] In other embodiments of the application, ring B is a bicyclic heterocycle, particularly a 9-11 membered bicyclic fused heterocycle, such as wherein ring G is a 5-6 membered heterocycle, such as moiety can be

[0048] In other embodiments of the application, ring B is a fused bicyclic ring, particularly a 9-11 membered fused bicyclic ring, such as wherein ring F is a 5-6 membered carbocycle or a 5-6 membered heterocycle, such as moiety can be

[0049] In particular, each R 101 through R 104 may be independently selected from the group consisting of: H, C1-C6 alkyl (e.g., -CH3, ), C1-C6 haloalkyl (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 hydroxysubstituted alkyl (e.g., ), C1-C6 alkoxy-substituted alkyl (e.g., ), C1-C6 aminosubstituted alkyl (e.g., ), C1-C6 alkylamino-substituted alkyl (e.g., ), C3-C 10 cycloalkyl (e.g., ), C4-C 10 cycloalkylalkyl (e.g., ), substituted or unsubstituted 4-10 membered heterocyclyl (e.g., ), C1-C 10 silyl-substituted alkyl (e.g., ), C1-C 10 silyl (e.g., ).

[0050] More particularly, each R 101 through R 104independently selected from: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0051] In particular, each R1may be independently selected from: C1-C6alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), halogen (e.g., F, CI, Br, I), C1-C6haloalkyl (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; in particular, the 4-10 membered heterocycle is a 4-6 membered heterocycle, e.g., In particular, the C3-C8cycloalkyl is a C3-C6cycloalkyl, e.g.,

[0052] In some embodiments of the application, R 102 is H.

[0053] More particularly, each R1may be independently selected from: C1-C6alkyl, halogen, C1-C6haloalkyl, cyano, nitro, azido, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101, -(CH2) t (4-8 membered heterocyclyl), -(CH2) t (C3-C6cycloalkyl), wherein t is an integer from 0 to 5, R 101 may be selected from: C1-C6alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), C1-C6haloalkyl (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C3-C6cycloalkyl (e.g., ), C4-C 10 cycloalkylalkyl

[0054] In some embodiments of the application, each R1is independently selected from: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH,

[0055] In one embodiment of the application, R0is

[0056] In some embodiments of the application, ring E 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), e.g., particularly a 5-7 membered nitrogen-containing heterocycle, e.g.,

[0057] In some embodiments of the application, moieties are

[0058] In particular, each R 201 to R 204 may be independently selected from: H, C1-C6alkyl (e.g., -CH3, ), C1-C6haloalkyl (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6hydroxy-substituted alkyl (e.g., ), C1-C6alkoxy-substituted alkyl (e.g. ), C1-C6alkylamino-substituted alkyl (e.g. ), C1-C6alkylamino-substituted alkyl (e.g. ), C3-C 10 cycloalkyl (e.g. ), C4-C 10 cycloalkylalkyl (e.g. ), substituted or unsubstituted 4-10 membered heterocyclyl (e.g. ),

[0059] More specifically, each R 201 through R 204 may be independently selected from H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0060] Specifically, R2may be selected from H, =0, C1-C6alkyl, C1-C6haloalkyl, halogen, cyano, nitro, azido, -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), -(CH2) j (4-10 membered heterocyclyl), -(CH2) j (C3-C 10 cycloalkyl), wherein j is an integer from 0 to 5; specifically, the 4-10 membered heterocycle is a 4-6 membered heterocycle, for example Specifically, the C3-C 10Cycloalkyl is C3-C6cycloalkyl, for example

[0061] More specifically, R2may be selected from the group consisting of: H, =0, C1-C6alkyl, C1-C6haloalkyl, halogen, halogen, cyano, nitro, azido, C1-C6alkoxy, C3-C6cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0062] In some embodiments of the application, R2is selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, hydroxyl, methoxy, ethoxy,

[0063] In some embodiments of the application, R0is selected from the group consisting of:

[0064] In one embodiment of the application, R0is -NR 001 R 002 wherein R 001 and R 002 are independently selected from the group consisting of: H, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxysubstituted alkyl, C1-C6alkoxysubstituted alkyl, C1-C6aminosubstituted alkyl, C1-C6alkaminosubstituted alkyl, C3-C6cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0065] Specifically, R 001 and R 002 are independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0066] In some embodiments of the application, R0is selected from the group consisting of:

[0067] In other embodiments of the application, R0is selected from the group consisting of: H, cyano, -0(C0-C 10 alkyl), -0(C1-C 10 silyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -OC(O)(C0-C 10 alkyl), -N(C0-C 10 alkyl)SO2(C0-C10 alkyl), -SO2N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -SO2(C0-C 10 alkyl), wherein the alkyl is optionally substituted with a group selected from halogen, cyano, hydroxyl, amino, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl; for example, R0is selected from: H, cyano, -OH, -COOH,

[0068] Specifically, R3to R5are independently selected from: H, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy-substituted alkyl, C1-C6alkylamino-substituted alkyl, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; more specifically, R3to R5are independently selected from: H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl.

[0069] In some embodiments of the application, R3is H.

[0070] In some embodiments of the application, R4is H.

[0071] In some embodiments of the application, R5is H.

[0072] Specifically, -Cy- can be selected from:

[0073] each R 10 is independently selected from: H, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy-substituted alkyl, C1-C6alkylamino-substituted alkyl, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl, 4-10 membered heterocyclyl; more specifically, each R 10 is independently selected from: H, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclobutyl.

[0074] In one embodiment of the application, L1is -C(O)NR3-, R3having the above defined meaning in the application.

[0075] In some embodiments of the application, L1is -C(O)NH-.

[0076] In another embodiment of the present application, L1is -Cy-, -Cy- having the above defined meaning in the present application.

[0077] In some embodiments of the present application, -Cy- is selected from:

[0078] In another embodiment of the present application, L1is a single bond.

[0079] In another embodiment of the present application, L1is -C(O)-.

[0080] Specifically, for the definition of L2, a and b are independently selected from: 0, 1, 2, 3, 4, 5.

[0081] Specifically, for the definition of L2, R L203 and R L204 may be independently selected from: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl.

[0082] Specifically, L2is a single bond or C2-C 10 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted with 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, wherein one or more H atoms in the alkylene are optionally and independently substituted with a group selected from: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; more specifically, L2is C2-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted with a group selected from: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-.

[0083] In some embodiments of the present application, L2is selected from: a single bond,

[0084] Specifically, for the definition of L3, c and d are independently selected from: 0, 1, 2, 3, 4, 5.

[0085] Specifically, for the definition of L3, R L303 and R L304It can be independently selected from: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0086] Specifically, L3 is a C1-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following groups: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, wherein one or more H atoms in the alkylene group are optionally and independently substituted with the following groups: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; in some embodiments of the present invention, L3 is methylene (-CH2-).

[0087] In one embodiment of the present invention, the compound has the following structure:

[0088] In one embodiment of the present invention, the compound has the following structure:

[0089] Among them, R 11 For C1-C 10 alkyl.

[0090] Specifically, R 11 It is a C1-C6 alkyl group, especially a C1-C3 alkyl group, such as methyl and ethyl.

[0091] In some embodiments of the present invention, the compound has the following structure:

[0092] In a second aspect of the invention, pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates, and deuterated compounds of the compounds described in the first aspect are provided.

[0093] In some embodiments of the present invention, the stereoisomer has the following structure:

[0094] In a third aspect of the present application, an intermediate compound is provided, which can be used for preparing the compound of the first aspect of the present application, wherein Y is -N(C0-C 10 alkyl)(C0-C 10 alkyl)(C0-C

[0095] wherein R 12 is alkyl;

[0096] A ring, B ring, X1, L1, L2, L3, R1, R0, and m have the definitions described in the first aspect of the present application.

[0097] Specifically, R 12 is C1-C6 alkyl, particularly C1-C3 alkyl, for example, methyl, ethyl.

[0098] In an embodiment of the present application, the intermediate compound has the following structure:

[0099] Specifically, the intermediate compound of Formula V can be converted into the compound of Formula II by amination (for example, by reacting with an alcoholic solution of ammonia or aqueous ammonia) in one step.

[0100] In a fourth aspect of the present application, a pharmaceutical composition is provided, which comprises the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0101] Specifically, the pharmaceutically acceptable excipients can be selected from one or more of disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption promoters, surfactants, flavoring agents, antioxidants, preservatives, and the like.

[0102] Specifically, in the pharmaceutical composition, the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, can be used alone or in combination with other types of active ingredients.

[0103] Specifically, the pharmaceutical composition can be administered by any suitable route, for example, by gastrointestinal administration (for example, oral, sublingual, rectal administration) or non-gastrointestinal administration (for example, intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, and the like). In some embodiments of the present application, the pharmaceutical composition is administered by intraocular administration (for example, eye drop administration, eye ointment administration, subconjunctival injection administration, intraocular injection administration).

[0104] In particular, the pharmaceutical composition can be any suitable dosage form, for example, a gastrointestinal administration dosage form, for example, including, but not limited to, tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; a non-gastrointestinal administration dosage form, for example, an injection administration dosage form: such as an injection (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), a respiratory administration dosage form: such as a spray, an aerosol, a powder spray, etc., a skin administration dosage form, such as an external solution, a lotion, an ointment, a plaster, a paste, a patch, etc., a mucous membrane administration dosage form: such as eye drops, eye ointment, nose drops, gargle, sublingual tablets, etc., a cavity administration dosage form: such as suppositories, aerosols, effervescent tablets, drops, dripping pills, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0105] In some embodiments of the present application, the above-mentioned pharmaceutical composition is an eye preparation, for example, eye drops, eye gel.

[0106] In particular, various dosage forms of the above-mentioned pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field. For example, the active ingredient is mixed with one or more pharmaceutically acceptable excipients, and then it is made into the desired dosage form.

[0107] In particular, in the above-mentioned pharmaceutical composition, the weight percentage of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, can be 0.1-99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, in particular, 1-30%.

[0108] In some embodiments of the present application, the pharmaceutical composition is an eye preparation I, which comprises:

[0109] a. the compound of the present application or a pharmaceutically acceptable salt thereof;

[0110] b. a potential solvent;

[0111] c. a pharmaceutically acceptable excipient;

[0112] Among them, the pharmaceutically acceptable excipient comprises: a solubilizing agent, a viscosity regulator, a buffer.

[0113] In particular, pharmaceutically acceptable salts of the compounds include, but are not limited to, aspartate, glutamate, malonate, salicylate, maleate, fumarate, succinate, benzoate, propionate, acetate, decanoate, stearate, oleate, hexanoate, adipate, octanoate, tartrate, citrate, malate, gluconate, glycolate, lactate, hydrobromate, hydrochlorate, sulphate, nitrate, phosphate, mesylate, besylate, tosylate, ethanesulphonate, hydroxyethanesulphonate, in particular mesylate, citrate, succinate, and in general salts forms include different molar ratios, for example the molar ratio of the compound to the acid can be 0.4-2:1, such as 2:1, 1:1 or 0.5:1.

[0114] In particular, the concentration of the compound in the ophthalmic formulation I is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml) (e.g. 0.01%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml) (the concentration of the compound described herein refers to the concentration in free form, even if it is added to the formulation composition in the form of a salt).

[0115] In particular, the concentration of the compound in the ophthalmic formulation I is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml) (e.g. 0.01%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml) (the concentration of the compound described herein refers to the concentration in free form, even if it is added to the formulation composition in the form of a salt).

[0116] In particular, the concentration of the compound in the ophthalmic formulation I is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml) (e.g. 0.01%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml) (the concentration of the compound described herein refers to the concentration in free form, even if it is added to the formulation composition in the form of a salt).

[0117] In one embodiment of the application, the solubilizing agent is a cyclodextrin, including a β-cyclodextrin derivative, a γ-cyclodextrin derivative, or a combination thereof, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or a combination thereof. Literature suggests that cyclodextrins can increase the contact time of a compound with the ocular surface and have the potential to reduce ocular irritation, as outlined in P. Jansook et al. Eur J Pharm Biopharm, 76, 208-214 (2010). T. J¨arvinen et al. J Ocul Pharmacol Ther, 11, 95-106 (1995). P. Jarho et al. J Pharm Pharmacol, 48, 264-270 (1996). P. Suhonen et al. Pharmaceutical Research, 12, 529-533 (1995). One particularly preferred β-cyclodextrin derivative is a hydroxyalkyl-β-cyclodextrin, such as hydroxypropyl-β-cyclodextrin (HP-β-CD). Another particularly preferred β-cyclodextrin derivative is a sulfobutyl ether-β-cyclodextrin, such as sulfobutyl ether-β-cyclodextrin (SBE-β-CD). One particularly preferred γ-cyclodextrin derivative is a hydroxyalkyl-γ-cyclodextrin, such as hydroxypropyl-γ-cyclodextrin (HP-γ-CD). Typically one of the three is employed. Sulfobutyl-β-cyclodextrin has compatibility issues with the viscosity modifier gellan gum, but can be used in formulations containing other viscosity modifiers than gellan gum. In some embodiments of the application, the solubilizing agent is hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0118] In particular, the solubilizing agent is present in the ophthalmic formulation I in a concentration of 1% w / v to 30% w / v (e.g. 1%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 20%, 25%, 30% w / v), in particular 5% w / v to 20% w / v.

[0119] Specifically, the viscosity adjusting agent is selected from the group consisting of cellulose derivatives (such as carboxymethyl cellulose, hydroxyethyl cellulose), carbomer, gellan gum, chitosan or its derivatives, xanthan gum, hyaluronic acid or its salts (such as sodium hyaluronate), alginic acid or its salts (such as sodium alginate), poloxamer series, polyvinyl alcohol, polyvinylpyrrolidone, or a combination thereof. Most of the viscosity adjusting agents are polymers with bioadhesion, which can interact with the mucus layer of the ocular surface at an appropriate concentration, prolong the residence time of the drug on the ocular surface, and at the same time have the effect of inhibiting the precipitation of the compound, and some amphiphilic polymers can also play the role of reducing surface tension and increasing the solubility of the compound. The residence time of small molecule compounds on the ocular surface after conventional eye drop administration is very short. This is an important factor that limits the sufficient exposure of the compound to the fundus. The residence time on the ocular surface is related to the viscosity of the preparation, and the literature (Patton.T.F.and Robinson, J.R. (1975) Ocular evaluation of polyvinyl alcohol vehicle in rabbits, J. Pharm. Sci. 64.1312-1316.) shows that in rabbits, the clearance rate of the ocular surface can be significantly reduced only when the viscosity of the preparation reaches >15 cps. This also suggests to us that appropriately increasing the viscosity of the eye drops is an important idea for optimizing the preparation. In addition, a large number of literature reports that the use of bioadhesive polymers has obvious delivery advantages, such as the reports of Hugo Almeida et al. Expert Opinion Drug Delivery (2013) 10(8), Jens Ceulemans et al. Journal of pharmaceutical sciences (2002), vol 91, No. 4. It is expected that the type of viscosity adjusting agent that can be selected is various, and according to the different types, it is mainly selected from the above-mentioned viscosity adjusting agents. Gellan gum is preferred as a viscosity adjusting agent due to its excellent ion-sensitive gel properties. In the presence of monovalent or divalent cations (such as sodium ions, potassium ions, calcium ions), it quickly gels and covers the surface to form a film structure, which is conducive to the long-term maintenance and release of the drug.

[0120] In some embodiments of the present application, the viscosity adjusting agent is poloxamer 188, and the concentration of poloxamer 188 in the ophthalmic preparation I is 0.01% w / v to 5% w / v (such as 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), especially 0.1% v / v to 2% w / v.

[0121] In some embodiments of the application, the viscosity modifier is gellan gum, which is present in the ophthalmic formulation I at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 0.5% w / v.

[0122] In some embodiments of the application, the viscosity modifier is carbomer, which is present in the ophthalmic formulation I at a concentration of 0.01% w / v to 1% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1% w / v), in particular 0.1% w / v to 0.6% w / v.

[0123] In some embodiments of the application, the viscosity modifier is poloxamer 188 and gellan gum, which is present at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 2% w / v.

[0124] In some embodiments of the application, the viscosity modifier is poloxamer 188 and carbomer, which is present at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 2% w / v.

[0125] In particular, the buffer comprises tromethamine, histidine, carnosine, phosphate or a combination thereof. For formulation compositions containing ion-sensitive gelling agents (such as gellan gum), components containing high amounts of monovalent or divalent cations, such as phosphates, should be avoided. In some embodiments of the application, the buffer is a tromethamine-hydrochloric acid buffer.

[0126] In particular, the buffers differ in their buffering capacity, but are generally present at a concentration of 5 mM to 100 mM (e.g. 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mM), for example 10 mM to 50 mM.

[0127] In one embodiment of the application, the pharmaceutically acceptable excipient further comprises a surfactant.

[0128] Specifically, the surfactant is selected from the group consisting of polyoxyethylene castor oil, tyloxapol, tween, polyoxyethylene 40 hydrogenated castor oil, or a combination thereof. Some commonly used surfactants that can be used in eye drops are suitable for use in the present application. In some embodiments of the present application, the surfactant is polyoxyethylene castor oil EL. In some embodiments of the present application, the surfactant is tyloxapol. In some embodiments of the present application, the surfactant is tween 80.

[0129] Specifically, the concentration of the surfactant in the ophthalmic formulation I is 0.1% w / v to 10% w / v (e.g. 0.1%, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 8%, 10% w / v), in particular 0.5% w / v to 2% w / v.

[0130] In one embodiment of the present application, the pharmaceutically acceptable excipient further comprises a pH adjusting agent for adjusting the pH of the ophthalmic formulation to a desired level. The pH adjusting agent includes acidic pH adjusting agent and basic pH adjusting agent. Specifically, the acidic pH adjusting agent comprises aspartic acid, glutamic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, propionic acid, acetic acid, decanoic acid, stearic acid, oleic acid, hexanoic acid, adipic acid, octanoic acid, tartaric acid, citric acid, malic acid, gluconic acid, glycolic acid, lactic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, isethionic acid, and more preferably the acidic pH adjusting agent is methanesulfonic acid, citric acid, succinic acid. The basic pH adjusting agent comprises sodium hydroxide, tromethamine, and more preferably tromethamine.

[0131] In one embodiment of the present application, the pharmaceutically acceptable excipient further comprises an osmotic pressure adjusting agent for adjusting the osmotic pressure of the ophthalmic formulation to a desired level. Specifically, the osmotic pressure adjusting agent is selected from the group consisting of sodium chloride, boric acid, glycerol, sorbitol, glucose. Sodium chloride should be avoided in the presence of gellan gum, and other osmotic pressure adjusting agents can be selected. The adjustment of the osmotic pressure should be adjusted to be close to or slightly higher than the physiological osmotic pressure as desired.

[0132] In one embodiment of the present application, the volume ratio of the mixture solution of b. the cosolvent and c. the pharmaceutically acceptable excipient is 1-10:90-99, for example 5:95.

[0133] Specifically, the pharmaceutically acceptable excipient can or can not contain a preservative, and the ideal form is free of preservatives. However, under certain prescription processes or packaging conditions, it can be impossible to avoid the use of preservatives. Potential preservatives include, but are not limited to, polyhexamethylene biguanide, polymeric quaternary ammonium compounds, chlorine-containing preservatives, chlorite preservatives, or others.

[0134] In one embodiment of the present application, the pharmaceutically acceptable adjuvant further comprises a solvent, in particular water, e.g. deionized water.

[0135] In one embodiment of the present application, the ophthalmic preparation I comprises:

[0136] a. the compound according to the present application or a pharmaceutically acceptable salt thereof;

[0137] b. polyethylene glycol 400;

[0138] c. hydroxypropyl-β-cyclodextrin, poloxamer 188, gellan gum, tromethamine-hydrochloric acid buffer, deionized water.

[0139] In one embodiment of the present application, the ophthalmic preparation I comprises:

[0140] a. the compound according to the present application or a pharmaceutically acceptable salt thereof;

[0141] b. polyethylene glycol 400;

[0142] c. hydroxypropyl-β-cyclodextrin, poloxamer 188, carbomer, tromethamine-hydrochloric acid buffer, deionized water.

[0143] In particular, the ophthalmic preparation I is a homogeneous preparation, e.g. a solution, an emulsion, a suspension, a gel, in particular a solution.

[0144] In one embodiment of the present application, the ophthalmic preparation I is a solution for ophthalmic use.

[0145] In particular, the ophthalmic preparation I has a pH of 5 to 9 (e.g. 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9), in particular 6 to 8, e.g. 6.5 to 7.5.

[0146] In particular, the ophthalmic preparation I has an osmolarity of 200 mOsm / kg to 500 mOsm / kg (e.g. 200, 250, 300, 350, 400, 450, 500 mOsm / kg), in particular 250 mOsm / kg to 450 mOsm / kg.

[0147] In one aspect, the present application provides a method for preparing the ophthalmic preparation I, comprising the following steps:

[0148] (1) adding the compound according to the present application or a pharmaceutically acceptable salt thereof to a latent solvent, dispersing;

[0149] (2) adding the solution of the pharmaceutically acceptable adjuvant to the mixture obtained in step (1), mixing;

[0150] Optionally, (3) a pH adjusting agent and / or an osmotic pressure adjusting agent is added to adjust the pH, the osmotic pressure of the mixture obtained in step (2) to a desired level.

[0151] Optionally, (4) a preservative is added.

[0152] Specifically, the dispersing in step (1) can be performed by ultrasonic treatment, mechanical stirring, magnetic stirring, vortex shaking, shearing, etc., particularly ultrasonic treatment.

[0153] Specifically, the dispersing in step (1) is to disperse to a state where the compound is dissolved or nearly dissolved, and if necessary, heating (e.g. to 50℃) can be performed to promote dissolution.

[0154] Specifically, the mixing in step (2) can be performed by ultrasonic treatment, mechanical stirring, magnetic stirring, vortex shaking, shearing, etc., particularly vortex shaking.

[0155] In one embodiment of the present application, step (2) comprises: adding the mixture obtained in step (1) into a buffer containing a solubilizing agent, a surfactant, a viscosity adjusting agent, and mixing.

[0156] In one embodiment of the present application, the viscosity adjusting agent is gellan gum, and before step (2), the pH of the mixture obtained in step (1) is adjusted to not less than 4 (e.g. 4, 5, 6, 7) to make the compound completely or partially dissolved.

[0157] In some embodiments of the present application, the pharmaceutical composition is an ophthalmic preparation II, and the preparation raw materials thereof comprise:

[0158] a. the compound or a pharmaceutically acceptable salt thereof according to the present application;

[0159] b. a pharmaceutically acceptable excipient;

[0160] c. a basic pH adjusting agent;

[0161] wherein the pharmaceutically acceptable excipient comprises: a solubilizing agent, a surfactant, a viscosity adjusting agent.

[0162] Specifically, the ophthalmic preparation II is prepared by mixing the preparation raw materials, particularly by the preparation method of the ophthalmic preparation II as described below.

[0163] In particular, pharmaceutically acceptable salts of the compounds include, but are not limited to, aspartate, glutamate, malonate, salicylate, maleate, fumarate, succinate, benzoate, propionate, acetate, decanoate, stearate, oleate, hexanoate, adipate, octanoate, tartrate, citrate, malate, gluconate, glycolate, lactate, hydrobromate, hydrochlorate, sulphate, nitrate, phosphate, methanesulphonate, benzenesulphonate, p-toluenesulphonate, ethanesulphonate, hydroxyethanesulphonate, in particular methanesulphonate, citrate, succinate, typically in different molar ratios, for example the molar ratio of compound to acid can be 0.4-2:1, such as 2:1, 1:1 or 0.5:1.

[0164] In particular, the concentration of the compound in the ophthalmic formulation II is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml) (0.01%, 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.2%, 1.4%, 1.5%, 1.6%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml) (the concentration of the compound described herein refers to the concentration of the free form, even if it is added to the formulation composition in the form of a salt).

[0165] In one embodiment of the application, the solubilizing agent is a cyclodextrin, including a β-cyclodextrin derivative, a γ-cyclodextrin derivative, or a combination thereof, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or a combination thereof. Literature suggests that cyclodextrins can increase the contact time of a compound with the ocular surface and have the potential to reduce irritation, as outlined in P. Jansook et al. Eur J Pharm Biopharm, 76, 208-214 (2010). T. J¨arvinen et al. J Ocul Pharmacol Ther, 11, 95-106 (1995). P. Jarho et al. J Pharm Pharmacol, 48, 264-270 (1996). P. Suhonen et al. Pharmaceutical Research, 12, 529-533 (1995). One particularly preferred β-cyclodextrin derivative is a hydroxyalkyl-β-cyclodextrin, such as hydroxypropyl-β-cyclodextrin (HP-β-CD). Another particularly preferred β-cyclodextrin derivative is a sulfobutyl ether-β-cyclodextrin, such as sulfobutyl ether-β-cyclodextrin (SBE-β-CD). One particularly preferred γ-cyclodextrin derivative is a hydroxyalkyl-γ-cyclodextrin, such as hydroxypropyl-γ-cyclodextrin (HP-γ-CD). Typically one of the three is employed. Sulfobutyl-β-cyclodextrin has compatibility issues with the viscosity modifier gellan gum, but can be used in formulations containing other viscosity modifiers than gellan gum. In some embodiments of the application, the solubilizing agent is hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0166] In particular, the solubilizing agent is present in the ophthalmic formulation II in a concentration of 1% w / v to 30% w / v (e.g. 1%, 2%, 4%, 5%, 6%, 8%, 10%, 12%, 14%, 15%, 20%, 25%, 30% w / v), in particular 5% w / v to 20% w / v.

[0167] Specifically, the viscosity adjusting agent is selected from the group consisting of cellulose derivatives (such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose), carbomer, gellan gum, chitosan or its derivatives, xanthan gum, hyaluronic acid or its salts (such as sodium hyaluronate), alginic acid or its salts (such as sodium alginate), poloxamer series, polyvinyl alcohol, polyvinyl pyrrolidone, or combinations thereof. Most of the viscosity adjusting agents are polymers with bioadhesion, which can interact with the mucus layer of the ocular surface at an appropriate concentration, prolong the residence time of the drug on the ocular surface, and at the same time have the effect of inhibiting the precipitation of the compound, and some amphiphilic polymers can also have the effect of reducing the surface tension and increasing the solubility of the compound. The residence time of small molecule compounds on the ocular surface after conventional eye drop administration is very short. This is an important factor that limits the sufficient exposure of the compound to the fundus. The residence time on the ocular surface is related to the viscosity of the preparation, and the literature (Patton.T.F.and Robinson, J.R. (1975) Ocular evaluation of polyvinyl alcohol vehicle in rabbits, J. Pharm. Sci. 64.1312-1316.) shows that in rabbits, the clearance rate of the ocular surface can be significantly reduced only when the viscosity of the preparation reaches > 15 cp. This also suggests to us that appropriately increasing the viscosity of the eye drops is an important idea for optimizing the preparation. In addition, a large number of literature reports that the use of bioadhesive polymers has obvious delivery advantages, such as the reports of Hugo Almeida et al. Expert Opinion Drug Delivery (2013) 10(8), Jens Ceulemans et al. Journal of pharmaceutical sciences (2002), vol 91, No. 4. It is expected that the type of viscosity adjusting agent can be selected, and according to the different types, the viscosity adjusting agent is mainly selected from the above-mentioned viscosity adjusting agents. Gellan gum is preferred as the viscosity adjusting agent due to its excellent ion-sensitive gel properties. In the presence of monovalent or divalent cations (such as sodium ions, potassium ions, calcium ions), it quickly gels and covers the surface to form a film structure, which is conducive to the long-term maintenance and release of the drug.

[0168] In some embodiments of the present application, the viscosity adjusting agent is poloxamer 188, and the concentration of poloxamer 188 in the ophthalmic preparation II is 0.01% w / v to 5% w / v (such as 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 2% w / v.

[0169] In some embodiments of the application, the viscosity modifier is a gellan gum, at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% w / v to 0.5% w / v, in the ophthalmic formulation II.

[0170] In some embodiments of the application, the viscosity modifier is a carbomer, at a concentration of 0.01% w / v to 1% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1% w / v), in particular 0.1% w / v to 0.6% w / v, in the ophthalmic formulation II.

[0171] In some embodiments of the application, the viscosity modifier is a poloxamer 188 and a gellan gum, at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 2% w / v, in the ophthalmic formulation II.

[0172] In some embodiments of the application, the viscosity modifier is a poloxamer 188 and a carbomer, at a concentration of 0.01% w / v to 5% w / v (e.g. 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular 0.1% v / v to 2% w / v, in the ophthalmic formulation II.

[0173] In some embodiments of the application, the viscosity modifier is xanthan gum, carboxylated chitosan, polyvinylpyrrolidone, polyvinyl alcohol or sodium hyaluronate.

[0174] In some embodiments of the present application, the viscosity adjusting agent is sodium hyaluronate, which can be high molecular weight sodium hyaluronate (average molecular weight greater than 2000 K Dalton, such as 2200, 2500, 3000, 3500, 4000, 5000 K Dalton), medium molecular weight sodium hyaluronate (average molecular weight 500 K to 2000 K Dalton, such as 600, 800, 1000, 1500, 1600, 1800, 2000 K Dalton), low molecular weight sodium hyaluronate (average molecular weight 10 K to 500 K Dalton, such as 10, 15, 20, 25, 30, 40, 50, 100, 200, 300, 400, 500 K Dalton), oligomeric sodium hyaluronate (less than 10 K Dalton, such as 1, 2, 4, 5, 6, 8, 10 K Dalton), and the concentration thereof in the ophthalmic preparation II is 0.01% w / v to 5% w / v (for example, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular, 0.1% v / v to 2% w / v.

[0175] In some embodiments of the present application, the viscosity adjusting agent is hydroxypropyl methylcellulose (such as E5 type, viscosity 400 cp type), and the concentration thereof in the ophthalmic preparation II is 0.01% w / v to 5% w / v (for example, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% w / v), in particular, 0.1% v / v to 2% w / v.

[0176] In some embodiments of the present application, the pharmaceutically acceptable adjuvant further comprises a buffer.

[0177] Specifically, the buffer comprises: tromethamine, histidine, carnosine, phosphate, or a combination thereof. For the formulation composition containing an ion-sensitive gel agent (such as gellan gum), components containing a large amount of monovalent or divalent cations, such as phosphate, should be avoided. In some embodiments of the present application, the buffer is a tromethamine-hydrochloric acid buffer.

[0178] Specifically, the buffers have different buffering capacities, but generally the concentration is 5 mM to 100 mM (for example, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 mM), for example, 10 mM to 50 mM.

[0179] In some embodiments of the present application, in the ophthalmic preparation II, a is the compound of the present application, and the preparation raw material further comprises: d. an acidic pH adjusting agent.

[0180] Specifically, the acidic pH adjuster comprises aspartic acid, glutamic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, propionic acid, acetic acid, decanoic acid, stearic acid, oleic acid, hexanoic acid, adipic acid, octanoic acid, tartaric acid, citric acid, malic acid, gluconic acid, glycolic acid, lactic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, isethionic acid, and more preferably the acidic pH adjuster is methanesulfonic acid, citric acid, succinic acid.

[0181] Specifically, the basic pH adjuster comprises sodium hydroxide, tromethamine, and preferably tromethamine.

[0182] Specifically, the amount of the acidic pH adjuster and the basic pH adjuster should be based on the solubility of the compound and the pH of the final formulation composition should be within the acceptable range.

[0183] Specifically, the surfactant is selected from the group consisting of polyoxyethylene castor oil, tyloxapol, tween, polyoxyethylene 40 hydrogenated castor oil, or a combination thereof. In some embodiments of the present application, the surfactant is polyoxyethylene castor oil EL. In some embodiments of the present application, the surfactant is tyloxapol. In some embodiments of the present application, the surfactant is tween 80.

[0184] Specifically, the concentration of the surfactant in the ophthalmic formulation II is 0.1% w / v to 10% w / v (e.g., 0.1%, 0.5%, 0.8%, 1%, 1.5%, 2%, 3%, 4%, 5%, 6%, 8%, 10% w / v), and particularly 0.5% w / v to 5% w / v.

[0185] In one embodiment of the present application, the pharmaceutically acceptable excipient further comprises an osmotic pressure adjuster for adjusting the osmotic pressure of the ophthalmic formulation to a desired level. Specifically, the osmotic pressure adjuster is selected from the group consisting of sodium chloride, boric acid, glycerol, sorbitol, glucose. Sodium chloride should be avoided in the composition with gellan gum, and other osmotic pressure adjusters can be selected. The adjustment of the osmotic pressure should be adjusted to be close to or slightly higher than the physiological osmotic pressure as needed.

[0186] In one embodiment of the present application, the pharmaceutically acceptable excipient can or can not contain a preservative, and the ideal form is free of preservatives. However, under certain prescription processes or packaging conditions, it can be impossible to avoid the use of preservatives. Potential preservatives include, but are not limited to, polyhexamethylene biguanide, polymeric quaternary ammonium compounds, chlorine-containing preservatives, chlorite preservatives, or others.

[0187] In one embodiment of the present application, the pharmaceutically acceptable excipient further comprises a chelating agent, such as amino acids (ethylenediaminetetraacetic acid, nitrilotriacetic acid), organic phosphonate (aminotri(methylene) phosphonic acid, diethylenetriamine penta(methylene) phosphonic acid, hydroxycarboxylic acids (gluconic acid, polyacrylic acid (PAA), maleic acid). Chelating agents, also known as complexing agents, have a coordinating atom that forms a chelate ring with a metal ion or atom, resulting in a chelate. A small amount of chelating agent is added to the formulation composition to chelate metal ions that can be introduced into the composition solution, thereby optimizing viscosity. In some embodiments of the present application, the chelating agent is ethylenediaminetetraacetic acid.

[0188] In particular, the concentration of the chelating agent in the ophthalmic formulation II is from 0.001% w / v to 1% w / v (e.g. 0.001%, 0.005%, 0.01%, 0.05%, 0.1%, 0.5%, 1% w / v).

[0189] In one embodiment of the present application, the pharmaceutically acceptable excipient further comprises a solvent, in particular water, such as deionized water.

[0190] In one embodiment of the present application, the pharmaceutically acceptable excipient comprises: hydroxypropyl-β-cyclodextrin, polyoxyl castor oil, poloxamer 188, gellan gum, tromethamine-hydrochloric acid buffer, deionized water.

[0191] In one embodiment of the present application, the ophthalmic formulation II is prepared from the following raw materials:

[0192] a. the compound according to the present application;

[0193] b. hydroxypropyl-β-cyclodextrin, polyoxyl castor oil, poloxamer 188, gellan gum, tromethamine-hydrochloric acid buffer, deionized water;

[0194] c. tromethamine;

[0195] d. succinic acid.

[0196] In another embodiment of the present application, the ophthalmic formulation II is prepared from the following raw materials:

[0197] a. the compound according to the present application;

[0198] b. hydroxypropyl-β-cyclodextrin, tyloxapol, gellan gum, tromethamine-hydrochloric acid buffer, deionized water;

[0199] c. tromethamine;

[0200] d. citric acid.

[0201] In another embodiment of the present application, the ophthalmic formulation II is prepared from the following raw materials:

[0202] a. a pharmaceutically acceptable salt of the compound of the present invention;

[0203] b. tyloxapol, hydroxypropyl-β-cyclodextrin, glycerol, deionized water;

[0204] c. Tromethamine.

[0205] In another embodiment of the present invention, the raw materials for the preparation of ophthalmic preparation II comprise:

[0206] a. the compound of the present invention or a pharmaceutically acceptable salt thereof;

[0207] b. tyloxapol, hydroxypropyl-β-cyclodextrin, glycerol, deionized water;

[0208] c. Tromethamine.

[0209] In another embodiment of the present invention, the raw materials for the preparation of ophthalmic preparation II comprise:

[0210] a. the compound of the present invention or a pharmaceutically acceptable salt thereof;

[0211] b. tyloxapol, hydroxypropyl-β-cyclodextrin, hydroxypropyl methylcellulose, glycerol, deionized water;

[0212] c. Tromethamine.

[0213] In another embodiment of the present invention, the raw materials for the preparation of ophthalmic preparation II comprise:

[0214] a. the compound of the present invention or a pharmaceutically acceptable salt thereof;

[0215] b. tyloxapol, hydroxypropyl-β-cyclodextrin, sodium hyaluronate, glycerol, deionized water;

[0216] c. Tromethamine.

[0217] In particular, the ophthalmic preparation II is a homogeneous preparation, such as a solution, an emulsion, a suspension, a gel, in particular a solution.

[0218] In one embodiment of the present invention, the ophthalmic preparation II is an eye drop.

[0219] In particular, the pH of the ophthalmic preparation II is from 5 to 9 (e.g. 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9), in particular from 6 to 8, e.g. 6.5-7.5.

[0220] Specifically, the osmotic pressure of the ophthalmic preparation II is 200 mOsm / kg to 500 mOsm / kg (e.g., 200, 250, 300, 350, 400, 450, 500 mOsm / kg), particularly 250 mOsm / kg to 450 mOsm / kg.

[0221] In one aspect, the present application provides a method for preparing the ophthalmic preparation II, comprising the steps of:

[0222] (1) dispersing the compound described in the present application into a solution containing part of the pharmaceutically acceptable excipients;

[0223] (2) adding an acidic pH adjuster and mixing;

[0224] (3) adding the remaining pharmaceutically acceptable excipients and mixing;

[0225] (4) adding a basic pH adjuster; or,

[0226] The method for preparing the ophthalmic preparation II comprises the steps of:

[0227] (A) dispersing a pharmaceutically acceptable salt of the compound described in the present application into a solution containing pharmaceutically acceptable excipients;

[0228] (B) adding a basic pH adjuster.

[0229] Specifically, the part of the pharmaceutically acceptable excipients in step (1) is a solubilizer and a surfactant.

[0230] In one embodiment of the present application, the solution containing part of the pharmaceutically acceptable excipients in step (1) is an aqueous solution containing a solubilizer and a surfactant.

[0231] In one embodiment of the present application, the solubilizer is a cyclodextrin.

[0232] In one embodiment of the present application, the solution containing part of the pharmaceutically acceptable excipients in step (1) accounts for 50% of the total volume of the preparation, and the solution is an aqueous solution containing 2%-60% (w / v) (e.g., 2%, 10%, 30%, 40%, 50%, 60%) solubilizer and 0.2%-20% (w / v) surfactant.

[0233] Specifically, the dispersing in step (1) can be performed by ultrasonic treatment, mechanical stirring, magnetic stirring, vortex shaking, shearing, etc., particularly ultrasonic treatment.

[0234] Specifically, the mixing in step (2) can be performed by ultrasonic treatment, mechanical stirring, magnetic stirring, vortex shaking, shearing, etc.

[0235] Specifically, the amount of the acidic pH adjusting agent added in step (2) can be an amount to adjust the pH to 3-5 (3, 3.5, 4, 4.5, 5) to dissolve or nearly dissolve the compound.

[0236] Specifically, the partial pharmaceutically acceptable excipient in step (3) comprises a viscosity adjusting agent, a buffer; more specifically, step (3) is adding a buffer containing a viscosity adjusting agent and mixing.

[0237] Specifically, the buffer containing a viscosity adjusting agent in step (3) accounts for about 50% v / v of the total volume of the preparation.

[0238] In an embodiment of the present application, the volume ratio of the solution containing a partial pharmaceutically acceptable excipient in step (1) to the buffer containing a viscosity adjusting agent in step (3) is 50:50.

[0239] Specifically, the mixing in step (3) can be performed by ultrasonic treatment, mechanical stirring, magnetic stirring, vortex shaking, shearing, etc., in particular vortex shaking.

[0240] In some embodiments of the present application, after step (3), a step of adding an osmotic pressure adjusting agent to adjust the osmotic pressure is further included.

[0241] Specifically, the amount of the basic pH adjusting agent added in step (4) can be an amount to adjust the pH to a desired level of the preparation, for example, 5 to 9 (for example, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9), in particular, 6 to 8, for example, 6.5-7.5.

[0242] Specifically, the pharmaceutically acceptable excipient in step (A) comprises a solubilizing agent, a surfactant, a viscosity adjusting agent.

[0243] Specifically, the amount of the basic pH adjusting agent added in step (B) can be an amount to adjust the pH to a desired level of the preparation, for example, 5 to 9 (for example, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9), in particular, 6 to 8, for example, 6.5-7.5.

[0244] In some embodiments of the present application, in the ophthalmic preparation I and the ophthalmic preparation II, the compound is T002 to T175, for example:

[0245] In the fifth aspect of the present application, the use of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, in the preparation of a medicament for inhibiting the activity of protein tyrosine kinase is provided.

[0246] In particular, the protein tyrosine kinase can be VEGFR, EGFR, TIE2; in particular, the VEGFR activity is inhibited.

[0247] In particular, the drug is a drug that selectively inhibits VEGFR.

[0248] In a sixth aspect of the present application, there is provided a use of a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, in the manufacture of a medicament for preventing and / or treating a proliferative disease mediated by a protein tyrosine kinase.

[0249] In one embodiment of the present application, the disease is a tumor, in particular a malignant tumor (cancer), including, but not limited to, breast cancer, lung cancer (in particular non-small cell lung cancer), adenocarcinoma, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, myeloid dysplasia, mesothelioma, myelodysplastic syndrome, hematological malignancies.

[0250] In particular, the hematological malignancies include leukemia, lymphoma, multiple myeloma (MM).

[0251] In particular, the leukemia can be chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphocytic leukemia (ALL), acute myelocytic leukemia (AML), acute monocytic leukemia.

[0252] In particular, the lymphoma can be 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 large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma, NK / T-cell lymphoma, in particular diffuse large B-cell lymphoma (DLBCL). In particular, in the use, the treatment of the tumor includes killing the tumor, preventing metastatic spread of the tumor, and growth of micrometastases.

[0253] In one embodiment of the application, the disease is an ocular disease, including, but not limited to, diabetic retinopathy (including nonproliferative (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema); age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy); pathologic choroidal neovascularization (CNV) from any pathologic mechanism (i.e., high myopia, trauma, sickle cell (anemia) disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophies); pathologic retinal neovascularization from any pathologic mechanism (i.e., sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid-cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic retinal vasculitis, birdshot retinochoroidopathy, retinal angiitis, sarcoid, or toxoplasmosis); uveitis; retinal vein occlusion (central or branch); ocular trauma; surgical-induced edema; surgical-induced neovascularization; cystoid macular edema; ocular ischemia; retinopathy of prematurity; Coat's disease (Coats' disease, also known as exudative retinopathies, retinal telangiectasia); sickle cell retinopathy and / or neovascular glaucoma; retinoblastoma.

[0254] In some embodiments of the application, the disease is diabetic retinopathy, including nonproliferative (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema.

[0255] In other embodiments of the application, the disease is age-related macular degeneration (AMD), including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy.

[0256] In a seventh aspect of the application, there is provided a method of inhibiting the activity of a protein tyrosine kinase, comprising the step of administering to a subject in need thereof a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, and deuterated compound thereof, or a pharmaceutical composition of the fourth aspect of the application.

[0257] In particular, the protein tyrosine kinase can be VEGFR (e.g. VEGFR1, VEGFR2, VEGFR3), EGFR, TIE2, FGFR (e.g. FGFR1, FGFR2, FGFR3, FGFR4), PDGFR (e.g. PDGFRA, PDGFRB); in particular, the activity of VEGFR (in particular VEGFR2) is inhibited.

[0258] In particular, the method is a method of selectively inhibiting VEGFR.

[0259] In particular, the subject can be a mammal, in particular a human.

[0260] In particular, the method is performed in vivo, or in vitro.

[0261] In an eighth aspect of the present application, there is provided a method of preventing and / or treating a proliferative disease mediated by a protein tyrosine kinase, comprising the step of administering to a subject in need thereof a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or a pharmaceutical composition of the fourth aspect of the present application.

[0262] In particular, the disease is as described in the sixth aspect of the present application.

[0263] In particular, the subject can be a mammal, in particular a human.

[0264] In a ninth aspect of the present application, there is provided a method of inhibiting ocular neovascularization, retinal vascular leakage, comprising the step of administering to a subject in need thereof a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or a pharmaceutical composition of the fourth aspect of the present application.

[0265] In particular, the administration can be by any suitable mode of administration, in particular intraocular administration, such as eye drop administration, eye ointment administration, subconjunctival injection administration, intraocular injection administration, in particular eye drop administration.

[0266] In particular, the subject can be a mammal, in particular a human.

[0267] The present application provides a series of compounds, which have the ability to inhibit tyrosine kinases for anti-angiogenesis, in addition to effectively antagonizing the activities of VEGFR1, VEGFR2, VEGFR3 tyrosine kinases, having high selectivity for inhibiting EGFR tyrosine kinase activity, which can effectively reduce or even completely avoid side effects, in particular ocular side effects (such as epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosion and / or corneal edema, keratitis), and have very good application and research value. DETAILED DESCRIPTION

[0268] Unless otherwise defined, all scientific and technical terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0269] In the present application, the term "aliphatic group" refers to a straight-chained or branched hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a ring structure that is completely saturated or that contains one or more units of unsaturation, that is connected to the rest of the molecule by a single bond, (also referred to herein as "aliphatic cycle", "cycloalkyl"). Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl groups, and the like. 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.

[0270] The term "carbocycle" consists entirely of carbon atoms and can be classified as aliphatic cycle, aromatic cycle.

[0271] The term "alkyl" refers to a straight-chained or branched hydrocarbon chain radical that is not cyclic and that does not contain units of unsaturation, and that is attached to the rest 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, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, t-pentyl, n-hexyl, i-hexyl, and the like. If the alkyl group is substituted with a cycloalkyl group, it corresponds to a "cycloalkylalkyl", such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. If the alkyl group is substituted with an aryl group, it corresponds to an "aralkyl", such as benzyl, benzhydryl or phenethyl. If the alkyl group is substituted with a heterocyclyl group, it corresponds to a "heterocyclylalkyl". In the present application, a Coalkyl group refers to H, i.e. a C 0-10 alkyl includes H and C 1-10 alkyl.

[0272] The term "alkylene" refers to a hydrocarbon radical (divalent alkyl) derived from an alkane molecule missing two hydrogen atoms, either of which can be replaced by a bond to the rest of the molecule. It can be straight-chained or branched and attached to the rest of the molecule by a single bond. Typical alkylene groups herein 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, and the like. In the present application, a Coalkylene group refers to a single bond, i.e. a C 0-10 alkylene includes a single bond and C 1-10 alkylene.

[0273] The term "cycloalkyl" refers to an alicyclic hydrocarbon, such as a monocyclic and / or fused ring containing 1 to 4 rings, containing 3 to 18 carbon atoms, preferably 3 to 10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or adamantyl, and the like.

[0274] The term "alkoxy" refers to a substituent formed by the replacement of a hydrogen in a hydroxyl group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, for example methoxy, ethoxy, propoxy, butoxy, and the like.

[0275] The term "alkylamino" refers to a substituent formed by the replacement of one or both hydrogens in an amino group (-NH2) with an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0276] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0277] The term "haloalkyl" refers to a group formed by the replacement of one or more hydrogens in an alkyl group with a halogen atom (e.g., fluorine, chlorine, bromine, or iodine), for example -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0278] The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing mono- and / or fused aryl groups, such as C6-Ci8(e.g., C6, C8, C10, C12, C14, C16, C18) aryl groups containing 1 to 3 rings and 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, and the like. 12 The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing mono- and / or fused aryl groups, such as C6-Ci8(e.g., C6, C8, C10, C12, C14, C16, C18) aryl groups containing 1 to 3 rings and 6 to 18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, and the like.

[0279] The term "heterocyclyl" refers to a 3- to 18-membered ring radical comprising 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 tetracyclic, etc. polycyclic ring systems, which can include fused (two rings share two ring atoms), spiro (two rings share one ring atom), or bridged (two rings share more than two ring atoms) ring systems (excluding annulated rings). Heterocyclyl groups can be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present application contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms, and include, for example, coumarinyl, including 8-coumarinyl, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phtalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furopyridinyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofuropyridinyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present application contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiiranyl, azepinyl, oxazepinyl, diazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolizinyl, and quinolizinyl.

[0280] The term "optionally substituted" group can be 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, C 1-6 haloalkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-6 cycloalkyl, C 4-10 cycloalkylalkyl, C 6-10 aryl, C 6-10 arylalkyl, C 3-8 heterocyclyl, C 3-8 heterocyclylalkyl; t is 0, 1 or 2; each R' and R" is independently selected from H, halogen, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl; or R' and R" attached to the same nitrogen, together with the nitrogen atom, form a heterocyclic ring.

[0281] The term "pharmaceutically acceptable salt" includes both acid and base addition salts.

[0282] The term "acid addition salt" includes but is not limited to salts of mineral acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, as well as salts of organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids, for example acetate, galacterate, caprate, stearate, oleate, hexanoate, malate, glycolate, ethanesulfonate, isethionate 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, hydroiodide, acetate, propionate, caprylate, isobutyrate, edisylate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzene sulfonate, toluene sulfonate, phenylacetate, citrate, lactate, tartarate, and methanesulfonate, also included are salts of amino acids such as arginate, gluconate, galacturonate, aspartate, glutamate and the like. Acid addition salts can be prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt. The free base form can be regenerated by contacting the salt form with a base. The free base form can be isolated by conventional means.

[0283] The term "base addition salt" refers to salts of the metal or amine such as hydroxides of alkali and alkaline earth metals or with organic amines. Examples of metals useful as cations include but are not limited to sodium, potassium, magnesium, and calcium. Examples of appropriate amines include but are not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane- 1,2-diamine), N-methylglucamine and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt. The free acid form can be regenerated by contacting the salt form with an acid. The free acid form can be isolated by conventional means.

[0284] The term "stereoisomer" includes enantiomeric, diastereomeric, and geometric (or cis-trans) isomeric forms of the present compounds. Some of the compounds of the present application have a cyclic alkyl group which can be substituted on more than one carbon atom, in which case all geometric or regioisomeric forms, including cis- and trans-forms, and mixtures thereof, are within the scope of the present application.

[0285] The term "solvate" refers to a physical association between one or more solvent molecules and one or more of the compounds of the present application. The physical association can include ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the solid state form. Solvates include solution-phase and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0286] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, e.g., 1, 2, 3, 4, or 5 hydrogen atoms, are replaced by deuterium atoms (D).

[0287] It will be recognized that depending on the source of the chemical materials used in the synthesis, there will be some variation in the natural isotopic abundance in the synthesized compounds. Thus, the compounds of the application will inherently contain small amounts of isotopologues that are deuterated. Despite this variation, the concentration of stable hydrogen and carbon isotopes of natural abundance is very low and insignificant compared to the degree of stable isotopic substitution of the compounds of the application. See, e.g., Wada, E, et al., Seikagaku, 1994, 66: 15; Gannes, LZ, et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119: 725.

[0288] In the compounds of the application, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is designated specifically as "H" or "hydrogen," that position is to be understood to have hydrogen in its natural isotopic composition. Likewise, unless otherwise indicated, when a position is designated specifically as "D" or "deuterium," that position is to be understood to have deuterium in an abundance of at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation).

[0289] The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance of a particular isotope and the natural abundance.

[0290] In other embodiments, the compounds of the application have an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), 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).

[0291] The term "isotopologues" refers to substances in which the chemical structure differs from a particular compound of the application only in its isotopic composition.

[0292] The term "prodrug" means a form of a compound of Formula I which is suitable for administration to a patient with no undue toxicity, irritation, allergic response, and the like, and which is effective for its intended use, including esters, amides, and zwitterions. Prodrugs are converted to parent compounds in vivo, e.g., by hydrolysis in blood.

[0293] The terms "patient" or "subject" and the like are used interchangeably herein and refer to any animal or cell thereof, whether in vitro or in situ, treated according to the methods described herein. In particular, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys, humans, and particularly humans.

[0294] The term "treatment" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, arresting, and / or stopping one or more clinical symptoms of a disease after the onset of the disease.

[0295] The term "prevention" refers to avoiding, minimizing, or making it difficult for a disease to occur or develop by treatment prior to the onset of the disease.

[0296] The term "tumor" refers to an abnormal mass of tissue in which the growth of the mass exceeds and is not coordinated with the growth of normal tissue. A tumor can be "benign" or "malignant" depending on the following characteristics: degree of cellular differentiation (including morphology and function), rate of growth, local invasion, and metastasis. A "benign tumor" is generally well-differentiated, characterized by slower growth than malignant tumors, and remains localized to the site of origin. In addition, benign tumors do not have the ability to infiltrate, invade, or metastasize to distant sites. In some cases, certain "benign" tumors can later give rise to malignant tumors, possibly due to additional genetic changes in a subpopulation of neoplastic cells of the tumor, and these tumors are referred to as "pre-malignant tumors." A "malignant tumor" is generally poorly differentiated (anaplastic), and is characterized by rapid growth with progressive infiltration, invasion, and destruction of surrounding tissue. In addition, malignant tumors generally have the ability to metastasize to distant sites.

[0297] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).

[0298] The term "protein tyrosine kinase inhibitor" refers to a molecule that decreases, inhibits, or otherwise reduces one or more biological activities of a protein tyrosine kinase. The inhibition using a protein tyrosine kinase inhibitor does not necessarily indicate a complete abrogation of protein tyrosine kinase activity. Protein tyrosine kinase activity can be reduced by a significant amount, e.g., 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.

[0299] Unless otherwise indicated, numerical ranges expressed in the format "from x to y" are understood to include x and y. When for a particular

[0300] The disclosures of various publications, patents and published patent specifications, are hereby incorporated by reference in their entirety.

[0301] Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are known as the most potent vascular permeability agents and endothelial cell specific, playing a key role in the proliferation, migration and angiogenesis of endothelial cells. Angiogenesis is an important mechanism in many physiological and pathological processes, involving the proliferation, migration and survival of endothelial cells, which in turn leads to further capillary formation, ultimately promoting the formation of blood vessels. Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play an important role in angiogenesis associated with pathologies such as tumor development and ocular neovascular diseases. For example, the expression level of VEGF is positively correlated with the degree of vascularization of tumor tissue. VEGF acts on VEGFR receptors, activating the phosphorylation of VEGFR receptor tyrosine kinase and leading to abnormal cell signal transduction, thus promoting the proliferation of endothelial cells and the formation of new blood vessels, and is a major player in many different cancers and ocular diseases that accompany pathological neovascularization. However, despite efforts to design VEGFR receptor-specific molecules, some cross-reactivity with other "off-target" receptors is unavoidable, such as inhibition of TIE2 receptor (i.e., TEK tyrosine kinase), or EGFR receptor activity. Clinically, receptor tyrosine kinase inhibitors have been observed to cause adverse side effects to the eye because of the inhibition of EGFR-mediated corneal epithelial wound healing due to the inhibition of VEGFR and EGFR. In addition, TIE2 plays a crucial role in maintaining vascular integrity. Its inhibition can lead to weakened endothelial cell connections, promoting fluid leakage and ocular edema, impairing retinal blood flow and oxygen delivery, and potentially causing vision loss. The compounds of the present invention have a clear improvement in selectivity in inhibiting TIE2 and EGFR. Not only does it improve the antagonism of all VEGFR receptor (VEGFR1, VEGFR2, VEGFR3) tyrosine kinase activity, but it also significantly improves the selectivity of inhibiting TIE2 and EGFR receptor activity (as shown in the test examples).

[0302] VEGFR2 is the major receptor for VEGF-induced endothelial cell signaling. Upon binding of the ligand VEGF and receptor after development and / or tissue injury, VEGFR2 undergoes autophosphorylation and is activated, inducing angiogenesis and bypassing occluded blood vessels. Clinical treatments targeting the vascular endothelial growth factor VEGF-A / VEGFR2 signaling pathway have been shown to be an effective approach to treat ocular neovascular diseases such as wet-AMD. The compounds of the present application have significant inhibitory capacity on VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells to block the signal transduction of abnormal cells, thereby inhibiting neovascularization (as shown in the test examples). The major function from VEGFR receptor signaling is to promote the proliferation of endothelial cells and neovascularization, and the compounds of the present application show inhibitory capacity on VEGF-induced human endothelial cell proliferation at nanomolar concentration levels (as shown in the test examples). In summary, the compounds of the present application are a novel tyrosine kinase inhibitor. This novel tyrosine kinase inhibitor can be applied not only to the treatment of neovascular age-related macular degeneration and diabetic retinopathy, but also to tumor indication therapy by blocking the blood and nutrients supply required for tumor growth, leading to tumor cell death, by blocking tumor neovascularization.

[0303] Although the U.S. Food and Drug Administration (FDA) approved aflibercept (VEGF Trap-Eye) for the treatment of neovascular age-related macular degeneration and diabetic retinopathy, aflibercept is a 115 kDa fully human recombinant protein that requires intravitreal injection for administration. Frequent intravitreal injections are not only inconvenient for clinicians and patients, but also carry rare but serious injection-related risks (retinal detachment, endophthalmitis, intraocular inflammation, cataract, etc.), so many patients do not adhere to the injection schedule and the drug efficacy is poor. The compounds of the present invention (small molecule VEGFR tyrosine kinase inhibitors) represent an alternative approach to directly target VEGF in place of VEGF antibody biologies. The good clinical results of VEGF antibody biologies have validated the role of the VEGF pathway in neovascular age-related macular degeneration and diabetic retinopathy. Small molecule VEGFR tyrosine kinase inhibitors have many advantages over monoclonal antibodies. With its ability to inhibit all members of the VEGFR family, it can effectively inhibit VEGF signaling. It can be formulated as eye drops to avoid intravitreal injection, can cross the cell membrane and directly interact with the cytoplasmic domain of the receptor tyrosine kinase (RTK). And small molecule eye drops are more cost-effective than monoclonal antibodies. It is challenging to develop small molecule tyrosine kinase inhibitors for clinical use in age-related macular degeneration and diabetic retinopathy. One of the most critical challenges is to overcome the risk of "on-target" toxicity. Inhibition of VEGFR in healthy vasculature can lead to serious adverse events such as hypertension, bleeding, and thrombosis. Although there have been many clinical successes in oncology indications, the safety of oral VEGFR-2 inhibitors can be the main reason for the limited clinical use and / or development of small molecule tyrosine kinase inhibitors for clinical use in patients with age-related macular degeneration and diabetic retinopathy. Therefore, relative to oral VEGFR-2 inhibitors, topical eye drops can provide an effective therapy that limits systemic exposure and avoids the problem of on-target toxicity.

[0304] While topical ocular administration has proven to be a successful strategy for treating diseases associated with the anterior segment of the eye (e.g., glaucoma), there are currently no FDA-approved topical therapies for ocular diseases associated with the posterior tissues of the eye (e.g., neovascular AMD and diabetic retinopathy). This is largely due to the anatomical and physiological barriers that have evolved in the human eye to protect the eye from foreign substances. The tear film is one of the first obstacles to overcome. Compounds to the anterior segment of the eye can be rapidly washed away by the tear film, leading to nasolacrimal duct drainage, thus compounds following topical instillation can need to be rapidly absorbed. However, absorption / permeation into ocular tissues can also be challenging. One route of absorption involves permeation through the cornea. The cornea is composed of an epithelium containing tight junctions and alternating lipophilic and hydrophilic layers. Another route of absorption is permeation into the conjunctiva and then diffusion into the sclera. The sclera is a relatively more permeable ocular tissue. However, drugs that enter the conjunctiva tend to "lose" into the systemic circulation due to the highly vascularized nature of this tissue. Compounds exposed in the sclera have the potential to diffuse into the choroid. The choroid is the primary target tissue for neovascular AMD. Diffusion from the choroid to the retina (the target tissue for neovascular AMD) is further attenuated by the blood-retinal barrier (BRB). The BRB has similar functionality to the blood-brain barrier and can be a strong barrier to diffusion of compounds. Due to these anatomical and physiological barriers, it is estimated that less than 5% of the dose of a topical administration reaches the posterior tissues of the eye. Despite these challenges associated with topical administration, the present invention focuses on developing structure-activity relationships (SAR) related to ocular as well as blood exposure. With the compound-containing eye drop formulation, there can be effective delivery to the posterior tissues of the eye (as shown in the test examples). Since rapid degradation of the compounds in plasma was observed, on one hand, this indicates that the exposure of the compounds of the present invention in the posterior tissues of the eye is distributed from the instillation site, not from the systemic blood. On the other hand, the low systemic exposure of these compounds in plasma, or whole body, is beneficial to avoid systemic target toxicity issues. Also, the considerable exposure of the sclera tissue indicates that these compounds are effectively delivered to the posterior tissues of the eye (choroid and retina) mainly through the sclera. The compounds also have some exposure in the posterior tissues of the eye (choroid and retina) 8 hours after administration. The present invention provides new compounds that achieve sufficient drug concentration in the posterior segment of the eye (e.g., choroid and retina) to bind to the relevant receptors targeted to the eye, increase the bioavailability in the posterior segment of the eye, and improve the problems encountered in the ocular delivery of existing topical therapeutic agents.

[0305] One of the goals of medicinal chemistry is to improve the bioavailability and stability of compounds to improve efficacy. Bioavailability indicates the rate and extent to which a therapeutic agent is absorbed from a pharmaceutical form and becomes available at the site of action. Current tyrosine kinase (e.g. VEGFR1, VEGFR2 and VEGFR3) inhibitors have problems of low solubility and / or low kinase inhibitory activity, which greatly affect the bioavailability of such compounds and thus reduce efficacy. The present invention provides a compound that can have the advantage of improved solubility and / or significant kinase inhibitory activity (as shown in the test examples). In addition, the test results also provide the percentage of the compound of the present invention as free drug, i.e. not bound to melanin, which is able to interact with receptors in ocular tissues (as shown in the test examples). Ocular tissues containing melanin cells are located in the retinal pigment epithelium, choroid in the posterior segment of the eye, and ciliary body and iris in the anterior segment of the eye. Binding of a compound to melanin can affect the ocular pharmacokinetics after topical administration. The present invention provides a compound-containing eye drop preparation intended for the treatment of age-related macular degeneration and diabetic retinopathy. These are diseases in the posterior segment of the eye, and the compound-containing eye drop preparation aims to achieve effective delivery to the posterior segment of the eye. In these cases, the drug can bind to melanin tissue in the posterior segment of the eye (retinal pigment epithelium, choroid) or the anterior segment of the eye (ciliary body, iris). Many clinical drugs bind to melanin, thereby affecting their ocular pharmacokinetics. The rate of binding of a compound to melanin is an important factor in ocular pharmacokinetics and pharmacodynamics, and must be taken into account in drug discovery and development.

[0306] A major limitation of eye drops can be the need for high concentrations of the compound in the ocular formulation in order to achieve therapeutically effective drug levels in the posterior ocular tissues due to the limited permeability of the corneal and conjunctival barriers for many eye drops. Depending on the compound (molecule itself or high concentrations thereof), the ocular formulation can have side effects on the anterior ocular tissues (including the conjunctiva, cornea and / or lens) leading to various ocular surface injuries such as corneal epithelial defects and erosion. In particular, ocular side effects such as epithelial denaturation and defects, ulceration, corneal epithelial thinning, erosion and / or corneal edema, keratitis can be induced after treatment with EGFR antibody drugs which are clinically observed. EGFR is a major factor for wound healing of the human corneal epithelium. Therefore, it is necessary to select compounds for topical ocular formulations which avoid inhibition of EGFR activity. The compounds of the present invention are highly selective for inhibition of EGFR tyrosine kinase activity in addition to effectively antagonizing VEGFR1, VEGFR2, VEGFR3 tyrosine kinase activity (as shown in the test examples). The inventors used male Dutch Belted rabbits to assess the maximal tolerated dose (MTD) of eye drop administration of the compounds to help select the lowest possible toxic dose while achieving the highest possible efficacy dose for use in in vivo animal efficacy experiments. The results show that the maximal tolerated dose (MTD) on the third day of eye drop administration was 100 μg / eye for PAN90806 and 250 μg / eye or higher for T093. The inventors further assessed the ocular toxicity risk of T093 and PAN90806 by eye drop administration to rabbits for six consecutive days. The results show that no ocular abnormalities were observed in all rabbits in the T093 (250 μg / eye) group, while the MTD of the positive compound PAN90806 was reduced to 50 μg / eye. T078 and T116 were administered by eye drop for three consecutive days at a dose of 1000 μg / eye and the results of the toxicity risk assessment show that no ocular abnormalities were observed in all rabbits. Thus, the maximal tolerated dose (MTD) on the fourth day of eye drop administration was 1000 μg / eye or higher for T078 and T116.

[0307] The present invention provides a compound of Formula I, in particular of Formula II, III, and medical uses thereof.

[0308] In one embodiment (1) of the present invention, in Formula I, in particular of Formula II, III, L1is -C(O)NR3- or a single bond, Part is wherein R1comprises at least one of the following groups: C1-C6haloalkyl, cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5, E ring, R2have the above corresponding definitions of the present invention.

[0309] In particular, each R 101 and R 102 may be independently selected from the group consisting of: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxysubstituted alkyl, C1-C6 alkoxy- substituted alkyl, C1-C6 aminosubstituted alkyl, C1-C6 alkylamino- substituted alkyl, C3-C 10 cycloalkyl, C4-C 10 cycloalkylalkyl, substituted or unsubstituted 4-10 membered heterocyclyl, C1-C 10 silylalkyl, C1-C 10 silyl.

[0310] More particularly, each R 101 and R 102 may be independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0311] In some embodiments of the present invention, each R 101 and R 102 is independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0312] In some embodiments of the present invention, R 102 is H.

[0313] In some embodiments of the present invention, R 101 is selected from the group consisting of: methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F,

[0314] More specifically, R1 contains at least one of the following groups: C1-C6 haloalkyl, cyano, nitro, azide, -OR 101 -C(O)R 101 -NHC(O)R 101 -C(O)NHR 101 -NHR 101 -SR 101 -(CH2) t (4-8 membered heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), where t is an integer from 0 to 5.

[0315] More specifically, R1 may also contain a group selected from: C1-C6 alkyl groups (e.g., methyl, ethyl, n-propyl, isopropyl), halogens (e.g., F, Cl, Br, I). In some embodiments of the invention, L1 is -C(O)NR3- or a single bond. Part of Wherein, R1 contains at least one of the following groups: -CF3, -CHF2, -CH2F, Cyano, Nitro, Azide, -OH More specifically, R1 may also contain groups selected from the following: C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), halogen (e.g., F, Cl, Br, I).

[0316] In some embodiments of the present invention Some have the following structure: Among them, R 1b Selected from: C1-C6 haloalkyl, cyano, nitro, azide, -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)2R101 -SO3H, -(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl); more particularly, R 1b is selected from the group consisting of: C1-C6haloalkyl, cyano, nitro, azido, -OR 101 , -C(O)R 101 , -NHC(O)R 101 , -C(O)NHR 101 , -NHR 101 , -SR 101 , -(CH2) t (4-8 membered heterocyclyl), -(CH2) t (C3-C6cycloalkyl), wherein t is an integer from 0 to 5;

[0317] R 1c is selected from the group consisting of: H, F, C1-C6alkyl, cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl);

[0318] R 1a , R 1d , R 1e is selected from the group consisting of: H, C1-C6alkyl (e.g., methyl, ethyl, n-propyl, i-propyl), halogen (e.g., F, Cl, Br, I), C1-C6haloalkyl, cyano, nitro, azido, -OR 101 , -C(O)R 101 , -C(O)OR 101 , -NHC(O)OR101 , -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl);

[0319] each R 101 and R 102 is as defined above.

[0320] Further, R 1b may be selected from the group consisting of: -CF3, -CHF2, -CH2F, cyano, nitro, azido, -OH,

[0321] In some embodiments of the application, R 1b is -C(O)NR 101 R 102 wherein R 101 and R 102 are independently selected from the group consisting of: H, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl.

[0322] Further, R 1a and R 1e may be independently selected from the group consisting of: H, halogen (such as F, Cl), C1-C3 alkyl (e.g. methyl).

[0323] Further, R 1c may be selected from the group consisting of: H, F.

[0324] Further, R 1d may be selected from the group consisting of: H, halogen (such as F, Cl), C1-C3 alkyl (e.g. methyl).

[0325] In some embodiments of the application, moieties have the following structure:

[0326] In some embodiments of the application, L1is -C(O)NR3-, R0is

[0327] In some embodiments of the application, R0is selected from: H, cyano, -O(C0-C 10 alkyl), -O(C0-C 10 silyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -OC(O)(C0-C 10 alkyl), -N(C0-C 10 alkyl)SO2(C0-C 10 alkyl), -SO2N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -SO2(C0-C 10 alkyl), wherein the alkyl is optionally substituted with a group selected from: halo, cyano, hydroxyl, amino, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl; more particularly, R0is selected from: H, cyano, -OH, -COOH,

[0328] In some embodiments of the application, L2is C0-C 10 alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted with a group selected from: H, C1-C6alkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6alkoxy, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; more particularly, L2is C0-C6alkylene.

[0329] In some embodiments of the application, the compound has the structure: In particular

[0330] In some embodiments of the present application, L1is a single bond, L2is a single bond, and R0is H, i.e., the compound has the following structure: In particular has the above definition.

[0331] In some embodiments of the present application, the compound has the following structure:

[0332] In one embodiment (2) of the present application, in Formula I, and in particular, Formula II, III, L1is -C(O)NR3-, and B ring is a monocyclic heterocycle, in particular, a 5-6 membered monocyclic heterocycle, for example may be wherein R1has the above definition of the present application.

[0333] Specifically, each R1may be independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, halogen, cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5.

[0334] In some embodiments of the present application, each R1may be independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, halogen, -OH, C1-C6alkoxy.

[0335] More specifically, each R1may be independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH,

[0336] In some embodiments of the application, L1is -C(O)NR3-, R0is

[0337] In some embodiments of the application, R0is selected from the group consisting of: H, cyano, -O(C0-C 10 alkyl), -O(C1-C 10 silyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -OC(O)(C0-C 10 alkyl), -N(C0-C 10 alkyl)SO2(C0-C 10 alkyl), -SO2N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -SO2(C0-C 10 alkyl), wherein the alkyl is optionally substituted with a group selected from: halo, cyano, hydroxyl, amino, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl; more specifically, R0is selected from the group consisting of: H, cyano, -OH, -COOH,

[0338] In some embodiments of the application, L2is C0-C 10 alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted with a group selected from: H, C1-C6alkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6alkoxy, C3-C6cycloalkyl, C4-C 10Cycloalkylalkyl; more specifically, L2is C0-C6alkylene.

[0339] In some embodiments of the application, the compound has the structure:

[0340] In one embodiment (3) of the application, in Formula I, and in particular, Formulas II, III, L1is -C(O)NR3-, and B ring is a bicyclic ring, and in particular, a 9-11 membered fused bicyclic ring, such as may be wherein R1is as defined above.

[0341] In particular, each R1may be independently selected from the group consisting of: H, C1-C6alkyl, C1-C6haloalkyl, halogen, cyano, nitro, azido, -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), -(CH2) t (4-10 membered heterocyclyl), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5.

[0342] In some embodiments of the application, each R1may be independently selected from the group consisting of: H, C1-C6alkyl, C1-C6haloalkyl, halogen, -OH, C1-C6alkoxy.

[0343] More specifically, each R1is independently selected from the group consisting of: H, methyl, ethyl, n-propyl, i-propyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH, In some embodiments of the application, each R1is independently selected from the group consisting of: H, methyl, ethyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH.

[0344] In some embodiments of the application, L1is -C(O)NR3-, R0is

[0345] In some embodiments of the application, R0is selected from the group consisting of: H, cyano, -O(C0-C 10 alkyl), -O(C0-C 10 silyl), -N(C0-C 10 alkyl)(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -OC(O)(C0-C 10 alkyl), -N(C0-C 10 alkyl)SO2(C0-C 10 alkyl), -SO2N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -SO2(C0-C 10 alkyl), wherein the alkyl is optionally substituted with a group selected from: halo, cyano, hydroxyl, amino, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl; more particularly, R0is selected from the group consisting of: H, cyano, -OH, -COOH,

[0346] In some embodiments of the application, L2is C0-C 10 alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted with a group selected from: H, C1-C6alkyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6alkoxy, C3-C6cycloalkyl, C4-C 10 cycloalkylalkyl; more particularly, L2is C1-C6alkylene.

[0347] In some embodiments of the present invention, the compound has the following structure:

[0348] In one embodiment (4) of the present invention, in formula I, and especially in formulas II and III, L1 is -Cy-, and the B ring and R0 have the above-described definitions of the present invention.

[0349] In some embodiments of the present invention, L1 is -Cy-, and R0 is

[0350] In some embodiments of the present invention, L1 is -Cy- and R0 is -NR. 001 R 002 .

[0351] In some embodiments of the present invention, -Cy- is selected from:

[0352] In some embodiments of the present invention, L2 is a single bond or C2-C. 10 Alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted with groups selected from the following groups: -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 one or more H atoms in the alkylene are optionally and independently substituted with the following groups: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; more specifically, L2 is a C2-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-. Specifically, L2 may be selected from: single bonds,

[0353] Specifically, A part can have the following structure:

[0354] In some embodiments of the present invention Some have the following structure: More particularly, R1is selected from: C1-C6alkyl, halogen, C1-C6haloalkyl, cyano, nitro, azido, -0(C0-C 10 alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10 alkyl), -C(O)O(C0-C 10 alkyl), -OC(O)(C0-C 10 alkyl), -N(C0-C 10 alkyl)SO2(C0-C 10 alkyl), -SO2N(C0-C 10 alkyl)(C0-C 10 alkyl), -N(C0-C 10 alkyl)C(O)(C0-C 10 alkyl), -C(O)N(C0-C 10 alkyl)(C0-C 10 alkyl), -SO2(C0-C 10 alkyl), wherein said alkyl is optionally substituted by a group selected from: halogen, cyano, hydroxy, amino, C1-C6alkoxy, C1-C6alkylamino, C3-C6cycloalkyl; more particularly, R1is selected from: halogen (such as F, Cl, Br). In one embodiment of the application, Part is

[0355] In some embodiments of the application, the compound has the following structure:

[0356] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0357] Synthesis Example:

[0358] Example 1: Synthesis of compound T002

[0359] The synthesis route is as follows:

[0360] First step

[0361] (1-methyl-1H-indazol-3-yl)methanol

[0362] (1-methyl-1H-indazol-3-yl)methanol

[0363] 1-Methyl-1H-indazole-3-carboxylic acid I001 (2.0 g, 11.4 mmol) was dissolved in anhydrous THF (20 mL). The mixture was cooled to -78 °C under N2 protection, and DIBAL-H (22.8 mL, 1 M in hexane, 22.8 mmol) was added dropwise. The reaction mixture was slowly heated to room temperature and stirred for 1 hour. The reaction mixture was then cooled to 0 °C and quenched with 1 M HCl (30 mL) aqueous solution. The mixture was extracted separately 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-indazole-3-yl)methanol I002 (1.2 g, yellow liquid), yield: 65%.

[0364] MS-ESI calculated value [M+H] + 163.1, actual measurement 162.9.

[0365] Step 2

[0366] (1-methyl-1H-indazol-3-yl)methyl 4-methylbenzenesulfonate

[0367] Methyl (1-methyl-1H-indazol-3-yl)4-methylbenzenesulfonate

[0368] (1-Methyl-1H-indazole-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). The mixture was cooled to 0 °C under N2 (g) protection, and TsCl (1.6 g, 8.2 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction solution was washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 10:1) to give (1-methyl-1H-indazole-3-yl)4-methylbenzenesulfonate methyl ester I003 (400 mg, white solid), yield: 23%.

[0369] Step 3

[0370] dimethyl 2-(mercapto(methylthio)methylene)malonate

[0371] Dimethyl 2-(mercapto(methylthio)methylene)malonate

[0372] Under N2 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. After stirring the mixture in an ice-water bath for 30 minutes, carbon disulfide (2.3 g, 30.3 mmol) was added dropwise. The mixture was stirred in an ice-water bath for 1 hour. Dimethyl sulfate (3.8 g, 30.3 mmol) was then added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then heated to 25 °C and stirred for 2 hours to obtain crude 2-(mercapto(methylthio)methylene)malonate I005, which was used directly in the next step.

[0373] Step 4

[0374] methyl 3-hydroxy-5-(methylthio)isothiazole-4-carboxylate

[0375] methyl 3-hydroxy-5-(methylthio)isothiazol-4-carboxylic acid

[0376] Under N2 protection, sodium bicarbonate (3.0 g, 15.2 mmol) was dissolved in water (30 mL). Hydroxylamine-O-sulfonic acid (4.1 g, 36.4 mmol) was added dropwise in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes. Crude 2-(mercapto(methylthio)methylene)malonate I005 was added dropwise. The reaction mixture was stirred overnight at 25 °C. Acetonitrile was removed from the reaction system by vacuum concentration. The pH of the reaction system was adjusted to 1 using concentrated hydrochloric acid. The solid was obtained by filtration and washed with water (20 mL) and EA / PE (10:1, 20 mL). After drying, methyl 3-hydroxy-5-(methylthio)isothiazolyl-4-carboxylic acid I006 (4.7 g, yellow solid) was obtained. The two-step yield was 76%.

[0377] MS-ESI calculated value [M+H] + 206.3, actual measurement 205.9.

[0378] 1 H NMR (400MHz, DMSO-d6) δ = 11.90 (brs, 1H), 3.76 (s, 3H), 2.56 (s, 3H)

[0379] Step 5

[0380] methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate

[0381] 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0382] Methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate was prepared according to the procedure described in Example 1, Step 6, using methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate I007 as the starting material.

[0383] Step 6

[0384] methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0385] 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0386] Methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate was prepared according to the procedure described in Example 1, Step 6, using methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate I007 as the starting material.

[0387] Step 7

[0388] methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate

[0389] 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0390] A methanol solution of methyl 3-((ethoxycarbonyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid ester I008 was cooled to 0°C. 40 mL of an aqueous solution of 98% concentrated sulfuric acid (20 mL) was added dropwise to the reaction system, and the reaction mixture was stirred overnight at 60°C. Methanol was removed by vacuum concentration. The mixture was extracted separately 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 obtain a crude product. The crude product was slurried with n-hexane (50 mL) to obtain methyl 3-hydroxy-5-(methanesulfonyl)isothiazol-4-carboxylic acid ester I009 (3.1 g, yellow solid). Three-step yield: 74%.

[0391] MS-ESI calculated value [M+H] + 238.0, actual measurement 237.8.

[0392] 1 H NMR (400MHz, DMSO-d6) δ = 13.07 (brs, 1H), 3.86 (s, 3H), 3.57 (s, 3H).

[0393] Step 8

[0394] methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0395] 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[0396] Methyl 3-hydroxy-5-(methanesulfonyl)isothiazolium-4-carboxylate I009 (400 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) were dissolved in DMSO (10 mL). Methyl (1-methyl-1H-indazole-3-yl)-4-methylbenzenesulfonate I003 (537 mg, 1.7 mmol) was added, and the reaction mixture was stirred overnight at 25 °C. Water (50 mL) was added to the reaction mixture, and the mixture was extracted separately with ethyl acetate (50 mL x 2). The organic phase was washed successively 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 column chromatography (PE:EA = 1:1) to give methyl 3-((1-methyl-1H-indazole-3-yl)methoxy)-5-(methanesulfonyl)isothiazolium-4-carboxylate I010 (350 mg, white solid), yield: 54%.

[0397] MS-ESI calculated value [M+H] +382.1, actual measurement 381.9.

[0398] 1 H NMR (400MHz, DMSO-d6) δ = 7.91 (d, J = 10.8Hz, 1H), 7.49-7.44 (m, 1H), 7.91 (t, J = 9.6Hz, 1H), 5.83 (s, 2H), 4.08 (s, 3H), 3.85 (s, 3H), 3.63 (s, 3H).

[0399] Step 9

[0400] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0401] 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[0402] Methyl 3-((1-methyl-1H-indazole-3-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid ester I010 (270 mg, 0.7 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (1.2 g, 7.1 mmol) was added. The reaction mixture was stirred overnight at 65 °C. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 1:1) to give methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazole-3-yl)methoxy)isothiazol-4-carboxylic acid ester I011 (310 mg, yellow solid), yield: 93%.

[0403] MS-ESI calculated value [M+H] + 469.2, actual measurement 469.0.

[0404] 1 H NMR (400MHz, DMSO-d6) δ = 8.17 (t, J = 5.4Hz, 1H), 8.01 (d, J = 8.4Hz, 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=6.0Hz,2H),4.10(s,3H),3.88(s,3H),3.84(s,3H),3.78(s,3H).

[0405] Step 10

[0406] methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0407] methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0408] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate I011 (230 mg, 0.5 mmol) was dissolved in DCM / H2O (10 / 2 mL), DDQ (446 mg, 2.0 mmol) was added, the reaction system was stirred at 0 °C for 30 min. The reaction solution was washed with saturated sodium bicarbonate (10 mL), saturated brine (10 mL) successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the product methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate I012 (150 mg, yellow solid), yield: 96%.

[0409] MS-ESI calculated [M+H] + 319.1, found 319.0.

[0410] Tenth step

[0411] methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0412] methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0413] Dissolve 4-(pyrrolidin-1-yl)butan-1-amine (100 mg, 0.7 mmol) in anhydrous THF (5 mL), under N2protection, reduce to 0 °C, add CDI (113 mg, 0.7 mmol), stir the reaction at 0 °C for 40 min, continue to stir the reaction at 25 °C for 30 min, add DMSO (5 mL), remove THF under reduced pressure, add 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), stir the reaction at 25 °C overnight. Add water (20 mL) to the reaction, extract the mixture with ethyl acetate (20 mL x 2), wash the organic phase with saturated brine (60 mL) in turn, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product, which is purified by column chromatography (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%.

[0414] MS-ESI calculated value [M+H] + 487.2, found 487.0.

[0415] 1 H 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).

[0416] Twelfth step

[0417] 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0418] 3-((1 -methyl- 1 H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin- 1 - yl)butyl)ureido)isothiazole-4-carboxamide

[0419] In a microwave tube, methyl 3-((1 -methyl- 1 H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin- 1 - yl)butyl)ureido)isothiazole-4-carboxylate IO13 (170 mg, 0.35 mmol) was dissolved in anhydrous THF (1 mL), and ammonium hydroxide (7 N, 4 mL) was added. The mixture was stirred at 50 °C for 96 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by high-performance preparative chromatography (NaHC03) to give 3-((1 -methyl- 1 H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin- 1 - yl)butyl)ureido)isothiazole-4-carboxamide T002 (80 mg, white solid) in 49% yield.

[0420] MS-ESI calculated [M+H] + 472.2, found 472.2.

[0421] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0422] Example 2: Synthesis of compound T003

[0423] The synthesis route is as follows:

[0424] First step

[0425] methyl 3-(2-bromoethoxy)benzoate

[0426] 3-(2-bromoethoxy)benzoic acid methyl ester

[0427] Methyl 3-(2-bromoethoxy)benzoate I014 (3.0 g, 11.6 mmol) was dissolved in anhydrous THF (20 mL) under N2protection, 1M potassium tert-butoxide in tetrahydrofuran (23 mL, 23.2 mmol) was added, the mixture was stirred at room temperature overnight. The reaction was added with water (50 mL), the mixture was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain methyl 3-(vinyl oxy)benzoate I015 (1.7 g, colorless liquid), yield: 82%.

[0428] 1 H NMR (400 MHz, CDC13) 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).

[0429] Second step

[0430] methyl 3-(vinyloxy)benzoate

[0431] methyl 3-(vinyloxy)benzoate

[0432] Methyl 3-(2-bromoethoxy)benzoate I014 (3.0 g, 11.6 mmol) was dissolved in anhydrous THF (20 mL) under N2protection, 1M potassium tert-butoxide in tetrahydrofuran (23 mL, 23.2 mmol) was added, the mixture was stirred at room temperature overnight. The reaction was added with water (50 mL), the mixture was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain methyl 3-(vinyl oxy)benzoate I015 (1.7 g, colorless liquid), yield: 82%.

[0433] Third step

[0434] methyl 3-cyclopropoxybenzoate

[0435] methyl 3-cyclopropoxybenzoate

[0436] Under N2 protection, methyl 3-(vinyloxy)benzoate I015 (1.7 g, 9.6 mmol) was dissolved in anhydrous DCM (20 mL), and diiodomethane (10.2 g, 38.2 mmol) was added. The mixture was cooled to 0 °C, and diethylzinc (19 mL, 19.1 mmol) was added dropwise. The mixture was stirred overnight at room temperature. 1N dilute hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture separated into layers. The aqueous phase was extracted separately using DCM (20 mL x 2). The organic phases were combined and washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-cyclopropoxybenzoate I016 (1.1 g crude product, colorless liquid), which was used directly in the next step.

[0437] Step 4

[0438] (3-cyclopropoxyphenyl)methanol

[0439] (3-Cyclopropylphenyl)methanol

[0440] Under N2 protection, methyl 3-cyclopropoxybenzoate I016 (1.1 g, 6.8 mmol) was dissolved in anhydrous THF (10 mL), and LAH (327 mg, 8.6 mmol) was added in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes. The reaction solution was quenched with water (0.3 mL), and 15% sodium hydroxide (0.3 mL) and water (0.9 mL) were added sequentially. 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, and the crude product was purified by column chromatography (PE:EA = 8:1) to obtain (3-cyclopropylphenyl)methanol I017 (870 mg, colorless liquid), yield: 92%.

[0441] MS-ESI calculated value [M-OH] + 147.2, actual measurement 147.0.

[0442] 1 H NMR (400MHz, CDCl3) δ=7.26-7.24(m,1H),7.06(d,J=2.0Hz,1H),6.98-6.94(m,2H),4.67(s,2H),3.76-3.71(m,1H),0.81-0.76(m,4H).

[0443] Step 5

[0444] 3-cyclopropoxybenzyl 4-methylbenzenesulfonate

[0445] 3-Cyclopropoxybenzyl 4-methylbenzenesulfonate

[0446] (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). The mixture was cooled to 0 °C under N2 protection, and TsCl (1.3 g, 6.8 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction solution was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by column chromatography (PE:EA = 10:1) to give 3-cyclopropoxybenzyl 4-methylbenzenesulfonate I018 (481 mg, colorless liquid), yield: 29%.

[0447] Step 6

[0448] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0449] 3-((3-cyclopropoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid methyl ester

[0450] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylate 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 overnight at 25 °C. Water (20 mL) was added to the reaction mixture, and the mixture was extracted separately with ethyl acetate (25 mL x 2). The organic phase was washed successively with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to give methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazolium-4-carboxylate I019 (210 mg, yellow solid), yield: 55%.

[0451] MS-ESI calculated value [M+H] + 384.1, actual measurement 383.8.

[0452] 1H NMR (400MHz, CDCl3) δ = 7.31-7.27 (m, 1H), 7.13 (d, J = 2.0Hz, 1H), 7.05-7.01 (m, 2 H),5.46(s,2H),3.95(s,3H),3.75-3.72(m,1H),3.47(s,3H),0.80-0.76(m,4H).

[0453] Step 7

[0454] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0455] 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[0456] Methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(methanesulfonyl)isothiazolium-4-carboxylate 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 overnight at 60 °C. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 5:1) to give methyl 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylate I020 (182 mg, yellow solid), yield: 68%.

[0457] MS-ESI calculated value [M+H] + 471.1, actual measurement 470.9.

[0458] Step 8

[0459] methyl 5-amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylate

[0460] 5-Amino-3-((3-cyclopropoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0461] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4- carboxylate I020 (170 mg, 0.4 mmol) was dissolved in DCM / H20 (5 / 1 mL), DDQ (327 mg, 1.4 mmol) was added, the reaction system was stirred at 0 °C for 30 min. To the reaction solution, DCM (15 mL) was added, the mixture was washed with saturated aqueous sodium bicarbonate solution (15 mL), saturated brine (15 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (PE:EA = 4:1) to give the product methyl 5-amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylate I021 (110 mg, yellow solid) in 94% yield.

[0462] MS-ESI calculated [M+H] + 321.0, found 320.9.

[0463] Ninth step

[0464] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0465] 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0466] 4-(pyrrolidin-1-yl)butan-1 -amine (66 mg, 0.5 mmol) was dissolved in anhydrous THF (5 mL), under N2protection, reduced to 0 °C, CDI (76 mg, 0.5 mmol) was added, the reaction system was stirred at 0 °C for 40 min, and then at 25 °C for 30 min, DMSO (5 mL) was added, 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, the reaction system was stirred at 25 °C overnight. To the reaction solution, water (20 mL) was added, the mixture was extracted with ethyl acetate (20 mL x 2) successively, the organic phase was washed with saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM:MeOH = 10:1) to give 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I022 (120 mg, white solid) in 79% yield.

[0467] MS-ESI calculated [M+H] + 489.2, found 489.0.

[0468] 1 H NMR (400 MHz, DMSO-d6) δ = 10.41 (br s, 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).

[0469] Tenth step

[0470] 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0471] 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 ammonium hydroxide (7 N, 6 mL) was added, and the mixture was stirred at 50 °C for 96 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified using high-performance preparative chromatography (NaHC03) to give 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide T003 (120 mg, white solid), yield: 59%.

[0472] MS-ESI calculated [M+H] + 474.2, found 474.2.

[0473] 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).

[0474] Example 3: Synthesis of compound T004

[0475] The synthetic route is as follows:

[0476] First step

[0477] methyl 1-methyl-1H-indazole-4-carboxylate

[0478] 1-methyl-1H-indazole-4-carboxylic acid methyl ester

[0479] Under N2protection, 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, the mixture was stirred under ice water bath for 30 minutes, then iodomethane (2.4 g, 17.1 mmol) was added, the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with ice water (50 mL), the mixture was extracted with ethyl acetate (50 mL x 2), the organic phase was washed with saturated brine (60 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE:EA = 1:1) to obtain 1-methyl-1H-indazole-4-carboxylic acid methyl ester I023 (1.2 g, white solid), yield: 55%.

[0480] MS-ESI calculated value [M+H] + 472.2, found 472.2.

[0481] 1 H 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).

[0482] Second step

[0483] (1-methyl-1H-indazol-4-yl)methanol

[0484] (1-methyl-1H-indazol-4-yl)methanol

[0485] (1-methyl-1H-indazol-4-yl)methanol

[0486] MS-ESI calculated [M+H] + 163.1, found 163.0.

[0487] Third step

[0488] (1-methyl-1H-indazol-4-yl)methyl 4-methylbenzenesulfonate

[0489] (1-methyl-1H-indazol-4-yl)methyl 4-methylbenzenesulfonate

[0490] (1-methyl-1H-indazol-4-yl)methyl 4-methylbenzenesulfonate

[0491] Fourth step

[0492] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0493] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0494] Methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4- carboxylate was prepared according to the procedure described in Example 1, Step 4, using methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (400 mg, 1.7 mmol) and potassium carbonate (466 mg, 3.38 mmol) in DMSO (10 mL) and methyl (1-methyl-1H-indazol-4-yl)methanesulfonate I025 (537 mg, 1.7 mmol). The reaction mixture was stirred at 25 °C overnight. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (40 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 the crude product, which was purified by column chromatography (PE:EA = 1:1) to give methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I026 (410 mg, white solid), yield: 63%.

[0495] MS-ESI calculated [M+H] + 382.1, found 381.9.

[0496] 1 H NMR (400 MHz, DMSO-d6) d = 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).

[0497] Fifth step

[0498] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0499] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0500] Methyl 3-((1-methyl-1H-indazole-4-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 overnight at 65 °C. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE:EA = 1:1) to give methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazole-4-yl)methoxy)isothiazol-4-carboxylic acid ester I027 (450 mg, yellow solid), yield: 72%.

[0501] MS-ESI calculated value [M+H] + 469.2, actual measurement 469.0.

[0502] Step 6

[0503] methyl 5-amino-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0504] 5-Amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[0505] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazole-4-yl)methoxy)isothiazolium-4-carboxylic acid I027 (430 mg, 0.9 mmol) was dissolved in DCM / H2O (10 / 2 mL), and DDQ (834 mg, 3.7 mmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes. The reaction solution was washed successively with saturated sodium bicarbonate aqueous solution (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain methyl 5-amino-3-(((1-methyl-1H-indazole-4-yl)methoxy)isothiazolium-4-carboxylic acid I028 (240 mg, yellow solid), yield: 84%.

[0506] MS-ESI calculated value [M+H] + 319.1, actual measurement 319.0.

[0507] Step 7

[0508] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0509] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0510] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0511] MS-ESI calculated [M+H] + 487.2, found 487.0.

[0512] 1H NMR (400 MHz, DMSO-d6) δ = 10.41 (br s, 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).

[0513] Eighth Step

[0514] 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0515] 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0516] In a microwave tube, methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4- (pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I029 (210 mg, 0.4 mmol) was dissolved in anhydrous THF (2 mL), and ammonium hydroxide (7 N, 6 mL) was added. The mixture was stirred at 50 °C for 96 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified using high-performance preparative chromatography (NaHC03) 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) in 59% yield.

[0517] MS-ESI calculated [M+H] + 472.2, found 472.2.

[0518] 1H 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).

[0519] Example 4: Synthesis of compound T005

[0520] The synthetic route is as follows:

[0521] First step

[0522] 5-bromo-2-(bromomethyl)pyridine

[0523] 5-bromo-2-(bromomethyl)pyridine

[0524] (5-Bromopyridin-2-yl)methanol (2.5 g, 13 mmol) was dissolved in THF (30 mL), cooled to 0 °C, and PBr3(10.8 g, 39 mmol) was added. The reaction system was stirred at room temperature for about 16 hours. The reaction liquid was poured into water (60 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 5-bromo-2-(bromomethyl)pyridine I030 (4 g, crude) as a red oily liquid.

[0525] The product was confirmed by LCMS.

[0526] Second step

[0527] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0528] 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0529] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4- carboxylate

[0530] The product was confirmed by LCMS.

[0531] Step 3

[0532] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0533] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0534] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4- carboxylate

[0535] The product was confirmed by LCMS.

[0536] Step 4

[0537] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0538] 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0539] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4- carboxylate I032 (2.5 g, 5.1 mmol) was dissolved in DCM / H2O (10 / 2 mL), DDQ (4.6 g, 20.4 mmol) was added, the reaction system was stirred at 0 °C for 30 min. The reaction solution was washed with saturated aqueous sodium bicarbonate solution (50 mL), saturated brine (50 mL) successively, 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 / 1-3 / 1) to obtain the product 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I033 (1.3 g, 74.7% yield) as a yellow solid.

[0540] The product was confirmed by LCMS.

[0541] Fifth step

[0542] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0543] 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0544] Dissolve 4-(pyrrolidin-1-yl)butan-1-amine (170 mg, 1.2 mmol) in anhydrous THF (5 mL), cool to 0 °C under N2protection, add CDI (194 mg, 1.2 mmol), stir the reaction at 0 °C for 40 min, continue to stir at 25 °C for 30 min, add DMSO (5 mL), remove THF under reduced pressure, add 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), stir the reaction at 25 °C overnight. Add water (50 mL) to the reaction, extract the mixture with ethyl acetate (50 mL x 3), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, purify the crude product using a 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).

[0545] The product is confirmed by LCMS.

[0546] Sixth step

[0547] 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0548] 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0549] Dissolve 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) in NH3 / MeOH (4 mL, 13 mol / L), stir the mixture at 60 °C for 16 h. Concentrate the reaction under reduced pressure to obtain the crude product, purify the crude product using high-performance preparative chromatography to obtain 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).

[0550] The product is confirmed by LCMS, H-NMR and C-NMR.

[0551] 1H NMR (400MHz, 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).

[0552] 13 C NMR (100MHz, 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.

[0553] Example 5: Synthesis of compound T006

[0554] The synthesis route is as follows:

[0555] first step

[0556] methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0557] 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[0558] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazol-4-carboxylic acid 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 system was stirred at 25 °C for 16 hours. Add water (30 mL) to the reaction solution, extract the mixture with ethyl acetate (50 mL x 3), wash the organic phase with water (50 mL) and saturated brine (50 mL) in sequence, dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, purify the crude product by column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain yellow solid product methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid ester I036 (0.5 g, 30.6% yield).

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

[0560] 1 H NMR (400MHz, 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).

[0561] Step 2

[0562] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0563] 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0564] Methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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. 1 N HCl solution (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid crude product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazol-4-carboxylic acid ester I037 (0.6 g, 98.0% yield).

[0565] The product was confirmed by LCMS and H-NMR.

[0566] 1 ¹H NMR (400MHz, 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

[0567] methyl 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0568] 5-Amino-3-((3,5-dimethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0569] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazolium-4-carboxylate I037 (0.6 g, 1.26 mmol) was dissolved in DCM / H2O (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 solution, and the mixture was 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 obtain the crude product. The crude product was purified by chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain the yellow solid product methyl 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazolium-4-carboxylate I038 (0.35 g, 85.3% yield).

[0570] The product was confirmed by LCMS and H-NMR.

[0571] 1 H NMR (400MHz, 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).

[0572] Step 4

[0573] methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0574] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[0575] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (230 mg, 1.62 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (262 mg, 1.62 mmol), stir the reaction at room temperature for 30 min, add DMSO (5 mL), remove THF under reduced pressure, add 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), stir the reaction at 25 °C for 16 h. Add water (20 mL) to the reaction, extract the mixture with ethyl acetate (10 mL x 3), wash the organic phase with water (10 mL) and saturated brine (20 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product. Purify the crude product by column chromatography (DCM / MeOH = 50 / 1 ~ 10 / 1) to give 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I039 (300 mg, 56.4% yield) as a colorless liquid.

[0576] The product is confirmed by LCMS and H-NMR.

[0577] 1 H NMR (400 MHz, CDC13) δ: 10.43 (s, 1H), 6.67 (d, 2H, J = 2.0 Hz), 6.41 (t, 1H, J = 2.0 Hz), 5.41 (s, 2H), 3.91 (s, 3H), 3.82 (s, 6H), 3.39 (t, 2H, J = 2.0 Hz), 3.08 (s, 3H), 2.94 (t, 2H, J = 7.2 Hz), 2.06-2.11 (m, 5H), 1.89-1.93 (m, 2H), 1.69-1.72 (m, 2H).

[0578] Fifth step

[0579] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0580] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0581] In a microwave tube, methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate I039 (300 mg, 0.61 mmol) was dissolved in THF (3 mL) and NH3 / MeOH (3 mL, 13 mol / L), and the mixture was stirred at 60 °C for 48 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance preparative chromatography (DCM / MeOH = 10 / 1, 0.1% NH3.H2O) to obtain 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).

[0582] The product was confirmed by LCMS, H-NMR and C-NMR.

[0583] 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 = 2.0 Hz), 6.46 (t, 1H, J = 2.4 Hz), 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).

[0584] 13 C 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.

[0585] Example 6: Synthesis of compound T007

[0586] The synthetic route is as follows:

[0587] First step

[0588] 5-(bromomethyl)benzo[d][1,3]dioxole

[0589] 5-(bromomethyl)benzo[d][1,3]dioxole

[0590] (2H-1,3-benzodioxono-5-yl)methanol (2.0 g, 13.2 mmol) was dissolved in DCM (20 mL), cooled to -40 °C, and PBr3 (3.56 g, 13.2 mmol) was added. The reaction mixture was stirred at -40 °C for about 20 minutes. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 5-(bromomethyl)benzo[d][1,3]dioxono-I040 (2 g, 70.8% yield) as a white solid.

[0591] The product was confirmed by LCMS and H-NMR.

[0592] 1 H NMR (400MHz, CDCl3) δ: 6.88-6.90 (m, 2H), 6.78 (d, 1H, J = 7.6Hz), 5.99 (s, 2H), 4.48 (s, 2H).

[0593] Step 2

[0594] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0595] 3-(benzo[d][1,3]dioxono-5-ylmethoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[0596] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazol-4-carboxylic acid 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]dioxonol I040 (1.0 g, 4.64 mmol) was added. The reaction system was stirred at room temperature for 2 hours. Add water (30 mL) to the reaction solution, and extract the mixture separately with ethyl acetate (30 mL x 3). Wash the organic phase successively with water (50 mL) and saturated brine (50 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure to obtain crude product, stir the crude product in MTBE (20 mL) for 20 minutes, filter, and dry the filter cake to obtain yellow solid product methyl 3-(benzo[d][1,3]dioxonol-5-ylmethoxy)-5-(methylsulfonyl)isothiazolyl-4-carboxylic acid ester I041 (0.85 g, 49.4% yield).

[0597] The product was confirmed by LCMS and H-NMR.

[0598] 1 H NMR (400 MHz, CDC13) δ: 6.92-6.95 (m, 2H), 6.80 (d, 1H, J = 8.0 Hz), 5.97 (s, 2H), 5.38 (s, 2H), 3.94 (s, 3H), 3.47 (s, 3H).

[0599] Third Step

[0600] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0601] 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0602] Methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I042 (1 g, 95.3% yield) was obtained as a yellow solid. LCMS: m / z = 520.1 (M+H)+, 518.1 (M-H)-.1H NMR (400 MHz, CDC13) δ: 7.18 (d, 1H, J = 8.0 Hz), 7.00 (s, 1H), 6.92-6.94 (m, 1H), 6.81 (d, 1H, J = 8.0 Hz), 6.45-6.50 (m, 2H), 5.97 (s, 2H), 5.34 (s, 2H), 4.29 (d, 1H, J = 6.0 Hz), 3.87 (s, 3H), 3.82-3.83 (m, 6H).

[0603] The product was confirmed by LCMS and H-NMR.

[0604] 1 H NMR (400 MHz, CDC13) δ: 6.92-6.95 (m, 2H), 6.80 (d, 1H, J = 8.0 Hz), 5.97 (s, 2H), 5.38 (s, 2H), 3.94 (s, 3H), 3.47 (s, 3H).

[0605] Fourth Step

[0606] methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate

[0607] methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate

[0608] methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate

[0609] The product was confirmed by LCMS and H-NMR.

[0610] 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).

[0611] Fifth step

[0612] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0613] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0614] Dissolve 4-(pyrrolidin-1-yl)butan-1 -amine (277 mg, 1.95 mmol) in anhydrous THF (5 mL), under N2protection, reduce to 0 °C, add CDI (316 mg, 1.95 mmol), stir the reaction at room temperature for 30 minutes, add DMSO (5 mL), remove THF under reduced pressure, add 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), stir the reaction at 25 °C for 16 hours. Add water (15 mL) to the reaction, extract the mixture with ethyl acetate (10 mL x 3), wash the organic phase with water (10 mL), saturated brine (20 mL) in turn, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product, purify the crude product using a chromatographic column (DCM / MeOH = 10 / 1) to obtain the 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) as a yellow liquid.

[0615] The product is confirmed by LCMS and H-NMR.

[0616] 1 H NMR (400 MHz, CDC13) δ: 10.27 (br s, 1H), 8.10 (br s, 1H), 7.00 (s, 1H), 6.94 (d, 2H, J = 7.6 Hz), 6.81 (d, 1H, J = 8.0 Hz), 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 = 6.0 Hz), 1.95 (s, 4H), 1.70-1.75 (m, 4H).

[0617] Sixth step

[0618] 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0619] 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0620] In a microwave tube, methyl 3-(benzo[d][l,3]dioxol-5-ylmethoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylate IO44 (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 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance preparative chromatography to obtain white solid product 3-(benzo[d][l,3]dioxol-5-ylmethoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide T007 (40 mg, 20.6% yield).

[0621] The product was confirmed by LCMS, H-NMR and C-NMR.

[0622] 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 = 1.2 Hz), 6.98-7.02 (m, 2H), 6.92 (d, 1H, J = 8.0 Hz), 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).

[0623] 13 C 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.

[0624] Example 7: Synthesis of compound T009

[0625] The synthetic route is as follows:

[0626] First step

[0627] 3-(bromomethyl)-l,5-dimethyl-lH-pyrazole

[0628] 3-(bromomethyl)-l,5-dimethyl-lH-pyrazole

[0629] (1,5-Dimethyl-1H-pyrazole-3-yl)methanol (2.0 g, 15.9 mmol) was dissolved in DCM (40 mL), cooled to 10 °C, and PBr3 (6.4 g, 23.8 mmol) was added. The reaction mixture was stirred at room temperature for about 16 hours. The reaction solution was poured into water (50 mL), and solid potassium carbonate was added to adjust the pH to 8–9. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole I049 (2.7 g, 90.1% yield) as a pale white solid.

[0630] The product was confirmed by LCMS and H-NMR.

[0631] 1 H NMR (400MHz, CDCl3) δ: 6.09 (s, 1H), 4.46 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H).

[0632] Step 2

[0633] methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0634] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[0635] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazol-4-carboxylic acid 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 system was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted separately with ethyl acetate (20 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 obtain the crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1-10 / 1) to obtain the yellow solid product methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid ester I050 (0.6 g, 67.4% yield).

[0636] The product was confirmed by LCMS and H-NMR.

[0637] 1 ¹H NMR (400MHz, 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

[0638] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0639] 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[0640] Methyl 3-((1,5-dimethyl-1H-pyrazole-3-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 the reaction was completed, the reaction solution was added to water (100 mL), the pH was adjusted to 4 with 4N HCl solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under pressure to give a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazole-3-yl)methoxy)isothiazol-4-carboxylic acid ester I051 (2.5 g, 99.6% yield).

[0641] The product was confirmed by LCMS and H-NMR.

[0642] 1 H NMR (400MHz, 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).

[0643] Step 4

[0644] methyl 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0645] methyl 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0646] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3- yl)methoxy)isothiazole-4-carboxylate I051 (1.5 g, 3.45 mmol) was dissolved in DCM / H2O (15 / 3 mL), DDQ (0.94 g, 4.14 mmol) was added portionwise at 0 °C, the reaction was stirred at room temperature for 10 min. Water (20 mL) was added to the reaction, extracted with DCM (10 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the crude product, the crude product was purified using a chromatography column (neutral alumina, PE / EA = 5 / 1-3 / 1-1 / 1-1 / 2) to give the yellow solid product methyl 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate I052 (0.78 g, 80% yield).

[0647] The product was confirmed by LCMS and H-NMR.

[0648] 1 H NMR (400 MHz, CDC13) 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).

[0649] methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0650] methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0651] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (281 mg, 1.97 mmol) in dry THF (25 mL) under N2protection, cool to 0 °C, add CDI (448 mg, 2.76 mmol), stir the reaction at room temperature for 60 min, add DMSO (25 mL), remove THF under reduced pressure, add 5-amino-3-((1,5-dimethyl-1 H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I052 (780 mg, 2.76 mmol) and potassium carbonate (546 mg, 3.95 mmol), stir the reaction at 25 °C for 16 h. Add water (100 mL) to the reaction, extract the mixture with ethyl acetate (50 mL x 3), wash the organic phase with water (100 mL), saturated brine (100 mL) successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the crude product, purify the crude product by preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1 % NH3.H2O) to give 3-((1,5-dimethyl-1 H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1 -yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I053 (700 mg, 56.2% yield) as a yellow solid.

[0652] The product was confirmed by LCMS and H-NMR.

[0653] 1 H NMR (400 MHz, CDC13) 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 = 5.6 Hz), 2.66 (s, 4H), 2.58 (t, 2H, J = 6.0 Hz), 2.26 (s, 3H), 1.89 (s, 4H), 1.68-1.69 (m, 4H).

[0654] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0655] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0656] In a microwave tube, methyl 3-((1,5-dimethyl-1 H-pyrazol-3-yl)methoxy)-5-(3-(4- (pyrrolidin-1 -yl)butyl)ureido)isothiazole-4-carboxylate I053 (250 mg, 0.55 mmol) was dissolved in NH3 / MeOH (10 mL, 9.5 mol / L) and the mixture was stirred at 60 °C for 16 h. The reaction was concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1 % NH3.H2O) to give the product 3-((1,5-dimethyl-1 H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1 -yl)butyl)ureido)isothiazole-4-carboxamide T009 (75 mg, 31 % yield) as a white solid.

[0657] The product was confirmed by LCMS, H-NMR and C-NMR.

[0658] 1 H NMR (400 MHz, CDC13) 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 = 3.6 Hz), 2.50-2.57 (m, 6H), 2.28 (s, 3H), 1.85 (s, 4H), 1.66 (d, 4H, J = 2.0 Hz).

[0659] 13 C NMR (100 MHz, CDC13) 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.

[0660] Example 8: Synthesis of compound T013

[0661] The synthesis route is as follows:

[0662] First step

[0663] 2-(bromomethyl)imidazo[1,2-a]pyridine

[0664] 2-(bromomethyl)imidazo[1,2-a]pyridine

[0665] {Imidazo[1,2-a]pyridin-2-yl}methanol (1.0 g, 6.7 mmol) was dissolved in DCM (40 mL), cooled to 0 °C, and PBr3(3.6 g, 13.4 mmol) was added. The reaction was stirred at room temperature for about 12 hours. After complete reaction, the crude product was directly concentrated under reduced pressure to obtain 2-(bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude) as a white product.

[0666] The product was confirmed by LCMS.

[0667] Second Step

[0668] methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0669] 3-(Imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0670] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (0.9 g, 3.8 mmol) and potassium carbonate (1.0 g, 7.6 mmol) were dissolved in DMF (20 mL), and 2-(bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude) was added. The reaction was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I072 (0.9 g, 66.7% yield) as a yellow solid product.

[0671] The product was confirmed by LCMS and H-NMR.

[0672] 1 H NMR (400 MHz, CDC13) δ: 8.12 (d, 1H, J = 6.8 Hz), 7.71 (s, 1H), 7.62 (d, 1H, J = 9.2 Hz), 7.21-7.23 (m, 1H), 6.82-6.85 (m, 1H), 5.70 (s, 2H), 3.96 (s, 3H), 3.49 (s, 3H).

[0673] Third Step

[0674] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0675] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0676] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0677] The product was confirmed by LCMS and H-NMR.

[0678] 1 H NMR (400 MHz, CDC13) δ: 8.09-8.10 (m, 2H), 7.68 (s, 1H), 7.60 (d, 1H, J = 9.2 Hz), 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 = 5.6 Hz), 3.86 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H).

[0679] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0680] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0681] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazolium[1,2-a]pyridin-2-methoxy)isothiazolium-4-carboxylic acid ester I073 (0.9 g, 2.0 mmol) was dissolved in DCM / H2O (25 / 5 mL). DDQ (1.8 g, 8.0 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After complete reaction, water (10 mL) was added to the reaction solution, and the mixture was washed with saturated sodium bicarbonate aqueous 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 methyl 5-amino-3-(imidazolium[1,2-a]pyridin-2-methoxy)isothiazolium-4-carboxylic acid ester I074 (250 mg, 37.3% yield).

[0682] The product was confirmed by LCMS and H-NMR.

[0683] 1 H NMR (400MHz, 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).

[0684] Step 5

[0685] methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0686] 3-(imidazolium[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[0687] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (125 mg, 0.88 mmol) in dry THF (6 mL) under N2protection, cool to 0 °C, add CDI (143 mg, 0.88 mmol), then stir the reaction at room temperature for 1 h, add DMSO (6 mL), remove most of the THF under reduced pressure, add 5-amino-3-(imidazo[1,2-a]pyridin-2- methoxy)isothiazole-4-carboxylic acid methyl ester I074 (200 mg, 0.64 mmol) and potassium carbonate (177 mg, 1.28 mmol), stir the reaction at room temperature for 12 h. After complete reaction, add water (40 mL) to the reaction, extract the mixture with dichloromethane (20 mL x 3), wash the organic phase with water (30 mL), saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the crude product, purify the crude product using preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1 % NH3.H2O) to give 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) as a white solid.

[0688] The product was confirmed by LCMS and H-NMR.

[0689] 1 H NMR (400 MHz, CDC13) δ: 10.10 (br s, 1H), 8.20 (br s, 1H), 8.11 (d, 1H, J = 6.8 Hz), 7.71 (s, 1H), 7.58-7.60 (m, 1H), 7.18 (t, 1H, J = 7.2 Hz), 6.79 (t, 1H, J = 6.8 Hz), 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).

[0690] Sixth step

[0691] 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0692] 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0693] In a microwave tube, methyl 3-(imidazo[l,2-a]pyridin-2-ylmethoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylate 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 reacted at 60 °C for 60 h in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH / NH3.H2O = 10 / 1 / 0.1) to obtain white solid product 3-(imidazo[l,2-a]pyridin-2-ylmethoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide T013 (25 mg, 17.1% yield).

[0694] The product was confirmed by LCMS, H-NMR and C-NMR.

[0695] 1 H NMR (400 MHz, CD3OD) δ: 8.43 (d, 1H, J = 6.8 Hz), 7.98 (s, 1H), 7.54-7.57 (m, 1H), 7.34-7.38 (m, 1H), 6.95 (t, 1H, J = 6.8 Hz), 5.60 (s, 2H), 3.27 (t, 2H, J = 6.4 Hz), 2.78 (s, 4H), 2.68-2.72 (m, 2H), 1.88-1.90 (m, 4H), 1.60-1.67 (m, 4H).

[0696] 13 C 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.

[0697] Example 9: Synthesis of compound T015

[0698] The synthesis route is as follows:

[0699] First step

[0700] (5-bromothiazol-2-yl)methyl 4-methylbenzenesulfonate

[0701] (5-bromothiazol-2-yl)methyl 4-methylbenzenesulfonate

[0702] (5-Bromo-1,3-thiazol-2-yl)methanol (1.0 g, 5.15 mmol) and Ts₂O (1.68 g, 5.15 mmol) were dissolved in DCM (10 mL). Under N₂ protection, the mixture was lowered to 0 °C, and triethylamine (1.04 g, 10.3 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After complete reaction, the reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by rapid chromatography (PE / EA = 20 / 1 to 2 / 1) to obtain the yellow solid product (5-bromothiazol-2-yl)-4-methylbenzenesulfonate methyl ester I081 (1.1 g, 61.5% yield).

[0703] The product was confirmed by LCMS and H-NMR.

[0704] 1 H NMR (400MHz, 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).

[0705] Step 2

[0706] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0707] 3-((5-bromothiazol-2-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid methyl ester

[0708] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylic acid ester I009 (0.8 g, 3.37 mmol) and potassium carbonate (0.93 g, 6.74 mmol) were dissolved in DMSO (10 mL). Methyl (5-bromothiazol-2-yl)-4-methylbenzenesulfonate I081 (1.1 g, 3.37 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a yellow solid, methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazolium-4-carboxylic acid ester I082 (1.3 g, 93.3% yield).

[0709] The product was confirmed by LCMS and H-NMR.

[0710] 1 H NMR (400MHz, CDCl3) δ: 7.71 (s, 1H), 5.70 (s, 2H), 4.00 (s, 3H), 3.52 (s, 3H).

[0711] Step 3

[0712] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0713] 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[0714] Methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid 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 the reaction was completed, the reaction solution was cooled to room temperature and added to water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The solutions were washed successively with 1N HCl solution (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid product, methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid ester I083 (1.5 g, 95.3% yield).

[0715] The product was confirmed by LCMS and H-NMR.

[0716] 1 H NMR (400MHz, 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).

[0717] Step 4

[0718] methyl 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylate

[0719] 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0720] Methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4- carboxylate I083 (1.5 g, 3.00 mmol) was dissolved in DCM / H2O (15 / 3 mL), DDQ (2.72 g, 12.0 mmol) was added portionwise at 0 °C, the reaction was stirred at room temperature for 40 min. After the reaction was completed, water (20 mL) was added to the reaction solution, which was extracted with dichloromethane (10 mL x 3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (PE / EA = 10 / 1 ~ 5 / 1) to obtain 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I084 (0.53 g, 47.6% yield) as a yellow solid.

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

[0722] 1 H NMR (400 MHz, DMSO-d6) δ: 7.99 (s, 2H), 7.89 (s, 1H), 5.56 (s, 2H), 3.73 (s, 3H).

[0723] Fifth step

[0724] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0725] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0726] To a solution of 4-(pyrrolidin-1-yl)butan-1-amine (245 mg, 1.72 mmol) in dry THF (20 mL) under N2protection, cool to 0 °C, add CDI (279 mg, 1.72 mmol), then stir the reaction at room temperature for 30 min, add DMSO (20 mL), remove most of the THF under reduced pressure, add 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), stir the reaction at room temperature for 16 h. After complete reaction, add water (60 mL) to the reaction, extract the mixture with ethyl acetate (60 mL x 3), wash the organic phase with water (40 mL) and saturated brine (50 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product, which is purified by column chromatography (DCM / MeOH = 30 / 1 ~ 20 / 1) to give 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) as a yellow solid.

[0727] The product is confirmed by LCMS and H-NMR.

[0728] 1 H NMR (400 MHz, CDC13) 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 = 5.2 Hz), 2.75 (s, 4H), 2.66 (t, 2H, J = 5.2 Hz), 1.96 (s, 4H), 1.73-1.77 (m, 4H).

[0729] Sixth step

[0730] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0731] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester was synthesized. 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) in a microwave tube, and the mixture was reacted at 60 °C for 16 hours in a sealed state. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was purified using preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain a 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).

[0732] The product was confirmed by LCMS, H-NMR, and C-NMR.

[0733] 1 H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.23 (t, 1H, J = 5.6 Hz), 7.92 (s, 1H), 7.68 (s, 1H), 6.14 (s, 1H), 5.66 (s, 2H), 3.13 (d, 2H, J = 5.6 Hz), 2.47 (s, 6H), 1.68 (s, 4H), 1.47 (s, 4H).

[0734] 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.

[0735] Example 10: Synthesis of compound T017

[0736] The synthesis route is as follows:

[0737] First step

[0738] 4-cyano-2-fluorobenzyl 4-methylbenzenesulfonate

[0739] 4-cyano-2-fluorobenzyl 4-methylbenzenesulfonate

[0740] To a solution of 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) in DMSO (10 mL) was added 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (1.42 g, 4.64 mmol) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (PE / EA = 10 / 1 ~ 2 / 1) to give 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I090 (1.4 g, 89.7% yield) as a yellow solid.

[0741] The product was confirmed by LCMS and H-NMR.

[0742] 1 H NMR (400 MHz, CDCl3) δ: 7.83 (d, 2H, J = 8.4 Hz), 7.46-7.54 (m, 2H), 7.34-7.39 (m, 3H), 5.17 (s, 2H), 2.49 (s, 3H).

[0743] Second step

[0744] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0745] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0746] To a solution of 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylic acid I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) in DMSO (10 mL) was added 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (1.42 g, 4.64 mmol) and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, water (30 mL) was added to the reaction mixture and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (PE / EA = 10 / 1 ~ 2 / 1) to give 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I090 (1.4 g, 89.7% yield) as a yellow solid.

[0747] The product was confirmed by LCMS and H-NMR.

[0748] 1 H NMR (400MHz, 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).

[0749] Step 3

[0750] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0751] 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[0752] Methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylic acid 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 the reaction was completed, the reaction solution was cooled to room temperature and added to water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to obtain the yellow solid product methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylic acid ester I091 (1.7 g, 98.3% yield).

[0753] The product was confirmed by LCMS and H-NMR.

[0754] 1 H NMR (400MHz, 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).

[0755] Step 4

[0756] methyl 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylate

[0757] 5-Amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0758] 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester I091 (1.3 g, 2.84 mmol) was dissolved in DCM / H2O (10 / 2 mL), and DDQ (2.58 g, 11.4 mmol) was added in portions at 0 °C. The reaction system was stirred at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated sodium bicarbonate aqueous 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 and dissolved in PE / EA (v / v = 3 / 1, 5 mL), filtered to leave the filter cake, washed with dichloromethane (2 mL), and dried to obtain the yellow solid product methyl 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazol-4-carboxylic acid ester I092 (0.6 g, 68.7% yield).

[0759] The product was confirmed by LCMS and H-NMR.

[0760] 1 H NMR (400MHz, DMSO-d6)δ:7.89-7.95(m,3H),7.72-7.79(m,2H),5.46(s,2H),3.73(s,3H).

[0761] Step 5

[0762] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0763] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[0764] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (417 mg, 2.93 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (475 mg, 2.93 mmol), then stir the reaction at room temperature for 30 min, add DMSO (5 mL), remove most of the THF under reduced pressure, add 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), stir the reaction at room temperature for 16 h. After complete reaction, add water (20 mL) to the reaction, extract the mixture with ethyl acetate (15 mL x 3), wash the organic phase with water (20 mL) and saturated brine (20 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I093 (350 mg, 37.7% yield) as a colorless oily liquid.

[0765] The product is confirmed by LCMS and H-NMR.

[0766] 1 H NMR (400 MHz, CDC13) δ: 10.20 (br s, 1H), 8.32 (br s, 1H), 7.74 (t, 1H, J = 7.6 Hz), 7.50 (d, 1H, J = 8.0 Hz), 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).

[0767] Sixth step

[0768] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0769] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0770] In a microwave tube, methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate I093 (350 mg, 0.74 mmol) was dissolved in NH3 / MeOH (4 mL, 10 mol / L), the mixture was stirred at 60 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, the crude product was purified using preparative thin layer chromatography (DCM / MeOH = 10 / 1) to obtain the product as a white solid, the product was stirred in acetonitrile (5 mL), and the solid product was left after filtration, which was dried to obtain 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide T017 (26 mg, 7.7% yield).

[0771] The product was confirmed by LCMS, H-NMR and C-NMR.

[0772] 1 H NMR (400 MHz, CD3OD) δ: 7.71 (d, 1H, J = 7.6 Hz), 7.59-7.65 (m, 2H), 5.64 (s, 2H), 3.26 (t, 2H, J = 6.4 Hz), 2.66 (s, 4H), 2.59 (t, 2H, J = 7.6 Hz), 1.84-1.87 (m, 4H), 1.58-1.64 (m, 4H).

[0773] 13 C 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.

[0774] Example 11: Synthesis of compound T022

[0775] The synthesis route is as follows:

[0776] First step

[0777] methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate

[0778] 5-bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester

[0779] Methyl 5-hydroxy-l-methyl-lH-pyrazole-3-carboxylate (10 g, 64 mmol) was dissolved in acetonitrile (50 mL), POBr3(55 g, 192 mmol) was added, the reaction was warmed to 80 °C and stirred for 24 h. After the reaction was completed, the mixture was poured into water (200 mL), the pH was adjusted to 8 with sodium bicarbonate, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, 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 obtain the white solid product methyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate I099 (5 g, 35.7% yield).

[0780] The product was confirmed by LCMS.

[0781] Second step

[0782] (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol

[0783] (5-bromo-l-methyl-lH-pyrazol-3-yl)methanol

[0784] Methyl 5-hydroxy-l-methyl-lH-pyrazole-3-carboxylate (10 g, 64 mmol) was dissolved in acetonitrile (50 mL), POBr3(55 g, 192 mmol) was added, the reaction was warmed to 80 °C and stirred for 24 h. After the reaction was completed, the mixture was poured into water (200 mL), the pH was adjusted to 8 with sodium bicarbonate, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, 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 obtain the white solid product methyl 5-bromo-l-methyl-lH-pyrazole-3-carboxylate I099 (5 g, 35.7% yield).

[0785] The product was confirmed by LCMS.

[0786] Third step

[0787] 5-bromo-3-(bromomethyl)-l-methyl-lH-pyrazole

[0788] 5-bromo-3-(bromomethyl)-l-methyl-lH-pyrazole

[0789] (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol II 100 (1.5 g, 7.89 mmol) was dissolved in dichloromethane (30 mL), PBr3(3.2 g, 11.9 mmol) was added at 0 °C, and the reaction was allowed to warm to room temperature for 16 h. After complete reaction, the reaction was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed with saturated sodium bicarbonate (50 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a colorless oily liquid product 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole II 101 (1.65 g, crude).

[0790] The product was confirmed by LCMS.

[0791] Fourth Step

[0792] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0793] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0794] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0795] The product was confirmed by LCMS and H-NMR.

[0796] 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).

[0797] Fifth Step

[0798] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0799] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[0800] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 about 5 hours. After the reaction was complete, the crude product was directly concentrated under reduced pressure and purified by column chromatography (PE / EA = 3 / 1) to obtain a white solid product, methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid ester I103 (1.7 g, 94.4%).

[0801] The product has been verified by LCMS.

[0802] Step 6

[0803] methyl 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0804] 5-Amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[0805] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate

[0806] The product was confirmed by LCMS.

[0807] Seventh step

[0808] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate

[0809] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate

[0810] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (344 mg, 2.42 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (392 mg, 2.42 mmol), then stir the reaction for 30 min, then stir the reaction at room temperature for 1 h, add DMSO (10 mL), remove most of the THF under reduced pressure, add 5-amino-3-((5-bromo-1 -methyl- 1 H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 1104 (600 mg, 1.73 mmol) and potassium carbonate (477 mg, 3.46 mmol), stir the reaction at room temperature for 16 h. After complete reaction, add water (50 mL) to the reaction, extract the mixture with ethyl acetate (20 mL x 3), wash the organic phase with water (30 mL), saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the crude product, purify the crude product using column chromatography (DCM / MeOH = 10 / 1,) to give 3-((5-bromo-1 -methyl- 1 H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1 -yl)butyl)ureido)isothiazole-4- carboxylic acid methyl ester 1105 (600 mg, 67.4% yield) as a white solid.

[0811] The product was confirmed by LCMS.

[0812] Eighth step

[0813] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0814] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0815] In a microwave tube, methyl 3-((5-bromo-l-methyl-lH-pyrazol-3-yl)methoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylate I105 (600 mg, 1.17 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was reacted at 60 °C for 16 hours in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain a white solid product, 3-((5-bromo-l-methyl-lH-pyrazol-3-yl)methoxy)-5-(3-(4- (pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide T022 (50 mg, 8.6% yield).

[0816] The product was confirmed by LCMS, H-NMR and C-NMR.

[0817] 1 H NMR (400 MHz, CDC13) 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).

[0818] 13 C NMR (100 MHz, CDC13) 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.

[0819] Example 12: Synthesis of compound T023

[0820] The synthesis route is as follows:

[0821] First step

[0822] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate

[0823] 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butoxycarbonyl)piperazin-1- yl)pyridin-2-yl)amino)isothiazole-4-carboxylic acid methyl ester

[0824] To a solution of methyl 3-(4-bromo-2,6-difluorophenoxy)-5-methylsulfonyl-1,2- thiazole-4-carboxylate 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. The reaction was stirred at 0 °C for 0.5 h and then at room temperature for 0.5 h. The reaction was poured into water (30 mL) and the mixture was 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 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert- butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylic acid methyl ester I107 (22.5 mg, 5% yield) as a yellow solid.

[0825] The product was confirmed by LCMS and HNMR.

[0826] 1 H NMR (400 MHz, CDCl3) δ: 10.80 (s, 1H), 8.11 (d, 1H, J = 2.4 Hz), 7.36-7.39 (m, 1H), 7.14-7.18 (m, 2H), 6.92 (d, 1H, J = 8.8 Hz), 5.48 (s, 2H), 3.84 (s, 3H), 3.62-3.64 (m, 4H), 3.11-3.13 (m, 4H), 1.52 (s, 9H).

[0827] Second step

[0828] tert-butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

[0829] tert-butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

[0830] Methyl 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate I107 (110 mg, 0.17 mmol) was dissolved in methanol (1 mL) and NH3 / MeOH (9 mL, 10 mol / L). The mixture was reacted at 60 °C for 72 h in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (PE / EA = 3 / 1) to obtain the product 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-aminocarbonylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester I108 (50.0 mg, 46% yield) as a yellow solid.

[0831] The product was confirmed by LCMS and H-NMR.

[0832] 1 H NMR (400 MHz, CDC13) δ: 11.52 (s, 1H), 8.10 (d, 1H, J = 2.4 Hz), 7.36-7.39 (m, 1H), 7.18-7.19 (m, 2H), 7.02 (s, 1H), 6.94 (d, 1H, J = 8.4 Hz), 5.56 (s, 2H), 5.29 (s, 1H), 3.61-3.64 (m, 4H), 3.10-3.12 (m, 4H), 1.58 (s, 9H).

[0833] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0834] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0835] tert-Butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4- aminocarbonylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate I108 (80.0 mg, 0.13 mmol) was dissolved in HCl / MeOH (5 mL, 8 mol / L), the mixture was stirred at 25 °C for 1.0 hour. The reaction solution was concentrated under reduced pressure, the residue was added water (10 mL) and adjusted pH value to 9.0 with aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH = 20 / 1) to give the 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) as a white solid.

[0836] The product was confirmed by LCMS, H-NMR and C-NMR.

[0837] 1 H NMR (400 MHz, CDCl3) δ: 11.48 (s, 1H), 8.09 (d, 1H, J = 2.8 Hz), 7.34-7.37 (m, 1H), 7.18-7.19 (m, 2H), 7.02 (s, 1H), 6.93 (d, 1H, J = 8.8 Hz), 5.56 (s, 2H), 5.31 (s, 1H), 3.13-3.14 (m, 4H), 3.08-3.09 (m, 4H).

[0838] 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.

[0839] Example 13: Synthesis of compound T024

[0840] The synthesis route is as follows:

[0841] First step

[0842] 6-aminopyridin-3-ol

[0843] 6-aminopyridin-3-ol

[0844] Dissolve 5-methoxypyridin-2-amine (2.8 g, 22.6 mmol) in 48% aq. HBr (15 mL) and stir the reaction at reflux for 12 h. Cool the reaction to room temperature, pour into cold water (20 mL), adjust the pH to 7-8 with aq. Na2CO3solution, extract with EtOAc (40 mL x 10), dry the combined organic phases over anhydrous Na2SO4, and concentrate under reduced pressure to give the crude product 6-aminopyridin-3-ol 1109 as a black oil (1.3 g, 52.3% yield).

[0845] The product is confirmed by LCMS and HNMR

[0846] 1 H NMR (400 MHz, CDC13) δ: 8.62 (s, 1H), 7.50 (dd, 1H, J = 3.2, 0.8 Hz), 6.91 (dd, 1H, J = 8.8, 3.2 Hz), 6.34 (dd, 1H, J = 8.8, 0.8 Hz), 5.19 (s, 2H).

[0847] Second step

[0848] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-amine

[0849] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-amine

[0850] Dissolve 6-aminopyridin-3-ol 1109 (1.3 g, 11.8 mmol) in DMF (15 mL), add 1-(2-chloroethyl)pyrrolidine hydrochloride (2.0 g, 11.8 mmol) and NaOH (1.9 g, 47.2 mmol), and stir the reaction at 65 °C for 2.0 h. Cool the reaction to room temperature, pour into brine (40 mL), extract with DCM / MeOH = 10 / 1 (v / v, 30 mL x 10), dry the combined organic phases over anhydrous Na2SO4, and concentrate under reduced pressure to give the crude product. Purify the crude product by column chromatography on silica gel (DCM / MeOH = 50 / 1 to 10 / 1) to give the product 5-(2-pyrrolidin-1-yl-ethoxy)pyridin-2-amine 1110 as a black solid (1.3 g, 53.1% yield).

[0851] The product is confirmed by LCMS and HNMR

[0852] 1H NMR (400MHz, 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).

[0853] Step 3

[0854] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-carboxylate

[0855] 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidine-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester

[0856] At 0 °C, LiHMDS (1.4 mL, 1.4 mmol, 1 mol / L) was added dropwise to a THF (30 mL) solution of methyl 3-(4-bromo-2,6-difluorophenoxy)-5-methylsulfonyl-1,2-thiazolyl-4-carboxylic acid ester I178 (300 mg, 0.68 mmol) and 5-(2-pyrrolidine-1-ylethoxy)pyridine-2-amine I110 (155 mg, 0.75 mmol). The reaction mixture was stirred at 0-10℃ for 1.0 h. The reaction solution was poured into NH4Cl aqueous solution (40 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to obtain white solid product methyl 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidine-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid ester I111 (18 mg, 4.8% yield).

[0857] The product was confirmed by LCMS and H-NMR.

[0858] 1H NMR (400MHz, 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).

[0859] Step 4

[0860] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0861] 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidine-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide)

[0862] Methyl 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidone-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid 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 and reacted at 60 °C for 72 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give a white solid product 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidone-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide T024 (21 mg, 19.6% yield).

[0863] The product was confirmed by LCMS, H-NMR and C-NMR.

[0864] 1 H NMR (400MHz, 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=5.6Hz),2.96(t,2H,J=5.6Hz),2.69(m,4H),1.86(m,4H).

[0865] 13 C NMR(100MHz, 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.

[0866] Example 14: Synthesis of compound T026

[0867] The synthesis route is as follows:

[0868] first step

[0869] 5-(bromomethyl)benzofuran

[0870] 5-(bromomethyl)benzofuran

[0871] (1-Benzofuran-5-yl)methanol (3.0 g, 20.3 mmol) was dissolved in DCM (50 mL), cooled to 0 °C, and PBr3 (8.21 g, 30.4 mmol) was added. The reaction system was stirred at room temperature for about 2 hours. After the reaction was complete, the reaction solution was poured into water (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily liquid product 5-(bromomethyl)benzofuran I117 (2.5 g, crude product).

[0872] The product has been verified by LCMS.

[0873] Step 2

[0874] methyl 3-(benzofuran-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0875] 3-(benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[0876] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction solution, which was extracted with ethyl acetate (20 mL x 2), and the combined organic phases were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (PE / EA = 3 / 1) to obtain a white solid product, methyl 3-(benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I118 (1.5 g, 65.2% yield).

[0877] The product was confirmed by LCMS and H-NMR.

[0878] 1 H NMR (400 MHz, DMSO-d6) δ: 8.03 (d, 1H, J = 1.6 Hz), 7.79 (s, 1H), 7.64 (d, 1H, J = 8.4 Hz), 7.44 (dd, 1H, J = 8.8, 1.2 Hz), 7.00 (d, 1H, J = 1.2 Hz), 5.58 (s, 2H), 3.88 (s, 3H), 3.61 (s, 3H).

[0879] Third step

[0880] methyl 3-(benzofuran-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0881] 3-(benzofuran-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester

[0882] Methyl 3-(benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I118 (2 g, 5.44 mmol) was dissolved in THF (50 mL), and 2,4-dimethoxybenzylamine (4.0 g, 24 mmol) was added, and the reaction system was stirred at 65°C for 6 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1) to obtain a yellow solid product, methyl 3-(benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I119 (2.0 g, 81.0% yield).

[0883] The product was confirmed by LCMS.

[0884] Fourth step

[0885] methyl 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylate

[0886] 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester

[0887] Methyl 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylate II 19 (1.5 g, 3.30 mmol) was dissolved in DCM / H2O (20 / 4 mL), DDQ (1.37 g, 4.95 mmol) was added portionwise at 0 °C, the reaction system was stirred at room temperature for 20 min. After the reaction was completed, water (10 mL) was added to the reaction solution, which was washed with saturated aqueous sodium bicarbonate solution (25 mL), and the organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography (PE / EA = 5 / 1) to obtain 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester II 20 (0.45 g, 45% yield) as a yellow solid.

[0888] The product was confirmed by LCMS.

[0889] Fifth step

[0890] methyl 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0891] 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0892] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (392 mg, 2.76 mmol) in dry THF (10 mL) under N2protection, cool to 0 °C, add CDI (448 mg, 2.76 mmol), then stir the reaction at room temperature for 1 h, add DMSO (10 mL), remove most of the THF under reduced pressure, add 5-amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester 1120 (600 mg, 1.97 mmol) and potassium carbonate (545 mg, 3.95 mmol), stir the reaction at room temperature for 16 h. After complete reaction, add water (50 mL) to the reaction, extract the mixture with ethyl acetate (20 mL x 3), wash the organic phase with water (30 mL) and saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1121 (600 mg, 64.4% yield) as a yellow oily liquid.

[0893] The product is confirmed by LCMS.

[0894] Sixth step

[0895] 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0896] 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0897] In a microwave tube, dissolve 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1121 (600 mg, 1.27 mmol) in NH3 / MeOH (10 mL, 13 mol / L), seal the mixture and react at 60 °C for 16 h. Concentrate the reaction under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T026 (60 mg, 10.5% yield) as a white solid.

[0898] The product is confirmed by LCMS, H-NMR and C-NMR.

[0899] 1H NMR (400 MHz, CD3OD) δ: 7.78-7.79 (m, 2H), 7.53 (d, 1H, J = 8.8 Hz), 7.44 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 1.2 Hz), 5.54 (s, 2H), 3.25 (t, 2H, J = 6.0 Hz), 2.49-2.57 (m, 6H), 1.82 (s, 4H), 1.58-1.60 (m, 4H).

[0900] 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.

[0901] Example 15: Synthesis of compound T027

[0902] The synthetic route is as follows:

[0903] First step

[0904] 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene

[0905] 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene

[0906] [4-(difluoromethoxy)-3-fluorophenyl]methanol (3.0 g, 15.6 mmol) was dissolved in DCM (50 mL), reduced to 0 °C, and PBr3(6.33 g, 23.4 mmol) was added. The reaction system was stirred at room temperature for about 3 hours. After complete reaction, the reaction liquid was added to water (50 mL), extracted with dichloromethane (50 mL x 2), the combined organic phase was washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene I122 (1.8 g of crude product) as a colorless oily liquid.

[0907] The product was confirmed by LCMS.

[0908] Second step

[0909] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0910] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0911] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0912] The product was confirmed by LCMS and H-NMR.

[0913] 1 H NMR (400 MHz, DMSO-d6) δ: 7.55 (d, 1H, J = 1.6 Hz), 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)

[0914] Third step

[0915] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0916] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0917] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 system was stirred at 60 °C for 6 hours. After the reaction was completed, the crude product was directly concentrated under reduced pressure, and purified by rapid column chromatography (PE / EA = 5 / 1) to obtain the white solid product methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid ester I124 (2 g, 82.6% yield).

[0918] The product has been verified by LCMS.

[0919] Step 4

[0920] methyl 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylate

[0921] 5-Amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0922] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylic acid ester I124 (2.3 g, 4.62 mmol) was dissolved in DCM / H2O (20 / 4 mL). DDQ (1.92 g, 6.93 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for 20 minutes. After complete reaction, water (10 mL) was added to the reaction solution, and the mixture was washed with saturated sodium bicarbonate aqueous 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 rapid column chromatography (PE / EA = 5 / ) to obtain the yellow solid product methyl 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazolium-4-carboxylic acid ester I125 (0.6 g, 37.5% yield).

[0923] The product was confirmed by LCMS and H-NMR.

[0924] 1 H NMR (400MHz, 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)

[0925] Fifth step

[0926] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0927] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0928] To a solution of 4-(pyrrolidin-1-yl)butan-1-amine (343 mg, 2.42 mmol) in anhydrous THF (10 mL) under N2protection, cool to 0 °C, add CDI (491 mg, 2.42 mmol), then stir the reaction at room temperature for 1 h, add DMSO (10 mL), remove most of the THF under reduced pressure, add 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), stir the reaction at room temperature for 16 h. After the reaction is complete, add water (40 mL) to the reaction, extract the mixture with ethyl acetate (15 mL x 3), wash the organic phase with water (30 mL) and saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain 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) as a yellow oily liquid.

[0929] The product is confirmed by LCMS.

[0930] Sixth step

[0931] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0932] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0933] In a microwave-safe container, methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid ester I126 (600 mg, 1.20 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was reacted under sealed conditions at 60 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain a white solid product 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxamide T027 (60 mg, 10.3% yield).

[0934] The product was confirmed by LCMS, H-NMR and C-NMR.

[0935] 1 H NMR (400MHz, 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).

[0936] 13 C NMR(100MHz,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.

[0937] Example 16: Synthesis of compound T028

[0938] The synthesis route is as follows:

[0939] first step

[0940] methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0941] 3-((3-methoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid methyl ester

[0942] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the filter cake was left to stand after filtration and dried to obtain white solid product methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I128 (438 mg, 58.4% yield).

[0943] The product was confirmed by LCMS and H-NMR.

[0944] 1 H NMR (400 MHz, CDC13) δ: 7.32 (t, 1H, J = 8.0 Hz), 7.03-7.06 (m, 2H), 6.90 (dd, 1H, J = 8.4, 2.0 Hz), 5.49 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H).

[0945] Second step

[0946] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0947] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0948] Methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I128 (0.5 g, 1.4 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (2.3 g, 14 mmol) was added. The reaction system was stirred at 60°C for 2 hours. After the reaction was completed, the reaction solution was brought to room temperature and cold water (40 mL) was added, and the solid was left to stand after filtration and dried to obtain yellow solid product methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate I129 (500 mg, crude).

[0949] The product was confirmed by LCMS.

[0950] Third step

[0951] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0952] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0953] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0954] The product was confirmed by LCMS.

[0955] Fourth step

[0956] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0957] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0958] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (102 mg, 0.72 mmol) in dry THF (5 mL) under N2protection, the solution was cooled to 0 °C, CDI (117 mg, 0.72 mmol) was added, then the reaction was stirred at room temperature for 1 h, DMSO (6 mL) was added, most of the THF was removed under reduced pressure, 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 1130 (150 mg, 0.51 mmol) and potassium carbonate (141 mg, 1.02 mmol) were added, the reaction was stirred at room temperature for 1 h. After the reaction was completed, water (5 mL) was added to the reaction, the solid was filtered, the filter cake was dried to give the crude product, the crude product was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give the product 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1131 (75 mg, 31.8% yield) as a yellow solid.

[0959] The product was confirmed by LCMS and H-NMR.

[0960] 1 H NMR (400 MHz, CDC13) 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 = 7.6 Hz), 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).

[0961] Fifth step

[0962] 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0963] 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0964] In a microwave tube, methyl 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate 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 in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain white solid product 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide T028 (15 mg, 15.4% yield).

[0965] The product was confirmed by LCMS, H-NMR and C-NMR.

[0966] 1 H NMR (400 MHz, CDCl3) δ: 10.94 (br s, 1H), 7.82 (br s, 1H), 7.33 (t, 1H, J = 8.0 Hz), 7.19 (s, 1H), 7.03 (d, 1H, J = 7.6 Hz), 7.00 (d, 1H, J = 2.4 Hz), 6.92 (dd, 1H, J = 8.0, 2.4 Hz), 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).

[0967] 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.

[0968] Example 17: Synthesis of compound T029

[0969] The synthesis route is as follows:

[0970] First step

[0971] methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0972] 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0973] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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-l-methoxybenzene I132 (462 mg, 2.1 mmol) was added. The reaction was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction, and the solid was left to filter. The cake was dried to give the crude product as a yellow solid, 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I133 (500 mg, 63.2% yield).

[0974] The product was confirmed by LCMS and H-NMR.

[0975] 1 H NMR (400 MHz, CDC13) δ: 7.18-7.25 (m, 2H), 6.98 (t, 1H, J = 8.4 Hz), 5.42 (s, 2H), 3.98 (s, 3H), 3.92 (s, 3H), 3.49 (s, 3H).

[0976] Second step

[0977] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0978] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0979] Methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I133 (0.58 g, 1.5 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (2.5 g, 15 mmol) was added. The reaction was stirred at 60 °C for 2 hours. After the reaction was completed, the reaction was brought to room temperature and water (40 mL) was added. The solid was left to filter, and the cake was dried to give the product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate I134 (550 mg, 77.0% yield), as a yellow solid.

[0980] The product was confirmed by LCMS.

[0981] Step 3

[0982] methyl 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0983] 5-Amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[0984] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazolium-4-carboxylic acid ester I134 (500 mg, 1.08 mmol) was dissolved in DCM / H2O (5 / 1 mL). DDQ (983 mg, 4.32 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. After complete reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain a yellow solid product, methyl 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazolium-4-carboxylic acid ester I135 (220 mg, 65.1% yield).

[0985] The product has been verified by LCMS.

[0986] Step 4

[0987] methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0988] 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[0989] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (108 mg, 0.76 mmol) in dry THF (6 mL) under N2protection, the solution was cooled to 0 °C, CDI (123 mg, 0.76 mmol) was added, then the reaction was stirred at room temperature for 1 h, DMSO (6 mL) was added, most of the THF was removed under reduced pressure, 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 1135 (170 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added, the reaction was stirred at room temperature for 1 h. After the reaction was completed, water (5 mL) was added to the reaction, the solid was filtered and dried to give the crude product, which was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1136 (100 mg, 38.4% yield) as a yellow solid.

[0990] The product was confirmed by LCMS and H-NMR.

[0991] 1 H NMR (400 MHz, CDC13) δ: 10.25 (s, 1H), 8.24 (s, 1H), 7.25-7.28 (m, 1H,), 7.17 (d, 1H, J = 8.4 Hz), 6.97 (t, 1H, J = 8.4 Hz), 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).

[0992] Fifth step

[0993] 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0994] 3-((3-Fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[0995] In a microwave tube, methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate II 136 (140 mg, 0.28 mmol) was dissolved in NH3 / MeOH (3 mL, 9 mol / L), and the mixture was reacted at 60 °C for 16 hours in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain 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).

[0996] The product was confirmed by LCMS, H-NMR and C-NMR.

[0997] 1 H NMR (400 MHz, CD3OD) δ: 7.25-7.29 (m, 2H), 7.13 (d, 1H, J = 8.4 Hz), 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).

[0998] 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.

[0999] Example 18: Synthesis of compound T030

[1000] The synthesis route is as follows:

[1001] First step

[1002] 1-(bromomethyl)-2-fluoro-3-methoxybenzene

[1003] 1-(bromomethyl)-2-fluoro-3-methoxybenzene

[1004] (2-Fluoro-3-methoxyphenyl)methanol (0.5 g, 3.2 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and PBr3(1.0 g, 3.8 mmol) was added under nitrogen protection. The reaction was stirred at room temperature for about 1 hour. After the reaction was completed, the crude product was directly concentrated under reduced pressure to obtain white product 1-(bromomethyl)-2-fluoro-3-methoxybenzene I137 (1 g, crude).

[1005] The product was confirmed by LCMS.

[1006] Second step

[1007] methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1008] 3-((2-Fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[1009] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (0.8 g, 3.2 mmol) and potassium carbonate (1.8 g, 12.8 mmol) were dissolved in DMF (15 mL), and 1-(bromomethyl)-2-fluoro-3-methoxybenzene I137 (0.9 g, crude) was added. The reaction was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid product 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I138 (0.7 g, 58.3% yield).

[1010] The product was confirmed by LCMS and H-NMR.

[1011] 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).

[1012] Third step

[1013] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[1014] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[1015] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[1016] The product was confirmed by LCMS and H-NMR.

[1017] 1 H NMR (400 MHz, CDC13) δ: 8.13 (br s, 1H), 7.15-7.19 (m, 2H), 7.09 (t, 1H, J = 8.0 Hz), 6.94 (t, 1H, J = 8.0 Hz), 6.45-6.49 (m, 2H), 5.52 (s, 2H), 4.29 (d, 2H, J = 5.6 Hz), 3.92 (s, 3H), 3.87 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H).

[1018] Fourth Step

[1019] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[1020] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[1021] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazolium-4-carboxylic acid I139 (0.4 g, 0.86 mmol) was dissolved in DCM / H2O (12 / 2.4 mL), and DDQ (0.78 g, 3.4 mmol) was added in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After complete reaction, water (25 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin-layer chromatography (PE / EA = 2 / 1) to obtain the yellow solid product methyl 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazolium-4-carboxylic acid I140 (180 mg, 67.2% yield).

[1022] The product was confirmed by LCMS and H-NMR.

[1023] 1 H NMR (400MHz, 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).

[1024] Step 5

[1025] methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1026] 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[1027] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (116 mg, 0.82 mmol) in dry THF (6 mL) under N2protection, cool to 0 °C, add CDI (132 mg, 0.82 mmol), then stir the reaction at room temperature for 1 h, add DMSO (6 mL), remove most of the THF under reduced pressure, add 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 1140 (180 mg, 0.58) and potassium carbonate (160 mg, 1.16 mmol), stir the reaction at room temperature for 8 h. After complete reaction, add water (20 mL) to the reaction, extract the mixture with dichloromethane (10 mL x 3), wash the organic phase with water (30 mL) and saturated brine (30 mL) successively, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1141 (130 mg, 46.8% yield) as a yellow solid.

[1028] The product is confirmed by LCMS and H-NMR.

[1029] 1 H NMR (400 MHz, CDC13) δ: 10.10 (br, 1H), 7.90 (br, 1H), 7.08-7.15 (m, 2H), 6.94 (d, 1H, J = 1.6 Hz), 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 = 6.4 Hz), 1.91-2.00 (m, 4H), 1.68-1.72 (m, 4H).

[1030] Sixth step

[1031] 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[1032] 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[1033] In a microwave tube, methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4- (pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate II 141 (180 mg, 0.37 mmol) was dissolved in NH3 / MeOH (6 mL, 9 mol / L), and the mixture was reacted at 60 °C for 72 h in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O = 10 / 1 / 0.1) to obtain 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).

[1034] The product was confirmed by LCMS, H-NMR and C-NMR.

[1035] 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 = 5.6 Hz), 2.37-2.40 (m, 6H), 1.64-1.68 (m, 4H), 1.46 (s, 4H).

[1036] 13 C 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.

[1037] Example 19: Synthesis of compound T032

[1038] The synthesis route is as follows:

[1039] First step

[1040] 1-(bromomethyl)-2,3-dimethoxybenzene

[1041] 1-(bromomethyl)-2,3-dimethoxybenzene

[1042] (2,3-Dimethoxyphenyl)methanol (0.5 g, 2.97 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and PBr3 (0.27 g, 0.99 mmol) was added. The reaction system was stirred at below 10 °C for about 1 hour. After the reaction was complete, the reaction solution was poured into water (40 mL), extracted with dichloromethane, and the organic phases were combined. The mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product as a colorless oily liquid 1-(bromomethyl)-2,3-dimethoxyphenyl I147 (0.6 g, 87.3% yield).

[1043] The product was confirmed by LCMS and H-NMR.

[1044] 1 H NMR (400MHz, 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).

[1045] Step 2

[1046] methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1047] 3-((2,3-dimethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid methyl ester

[1048] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylate 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 solution, and the mixture was filtered to obtain a solid. The filter cake was washed with water and dried to obtain a crude product, a white solid, methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazolium-4-carboxylate I148 (0.6 g, 72.0% yield).

[1049] The product was confirmed by LCMS and H-NMR.

[1050] 1H NMR(400MHz, 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).

[1051] Step 3

[1052] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[1053] 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[1054] Methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazolium-4-carboxylate 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 the reaction was completed, the reaction solution was added to water (30 mL), filtered to obtain a solid, the filter cake was washed with water, and dried to obtain a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazolium-4-carboxylate I149 (0.54 g, 88.4% yield).

[1055] The product was confirmed by LCMS and H-NMR.

[1056] 1 ¹H NMR (400MHz, 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

[1057] methyl 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[1058] 5-Amino-3-((2,3-dimethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[1059] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4- carboxylate II149 (0.6 g, 1.26 mmol) was dissolved in DCM / H20 (6 / 1.2 mL), DDQ (0.34 g, 1.52 mmol) was added portionwise at 0 °C, the reaction was stirred at room temperature for half an hour. After the reaction was completed, neutral alumina was added to the reaction solution, most of the solution was removed by reduced pressure concentration, the crude product was purified by column chromatography (neutral alumina, PE / EA = 10 / 1 ~ 1 / 1) to obtain the white solid product methyl 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate II150 (0.35 g, 85.3% yield).

[1060] The product was confirmed by LCMS and H-NMR.

[1061] 1 H NMR (400 MHz, CDC13) 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).

[1062] Fifth step

[1063] methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1064] methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1065] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (123 mg, 0.86 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (140 mg, 0.86 mmol), stir the reaction at room temperature for 1 h, add DMSO (5 mL), remove most of the THF under reduced pressure, add 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester 1150 (200 mg, 0.62 mmol) and potassium carbonate (170 mg, 1.23 mmol), stir the reaction at room temperature for 1 h. After complete reaction, add water (10 mL) to the reaction, filter to get a solid, wash the filter cake with water, dry to get the crude product as a white solid product 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1151 (200 mg, 65.8% yield).

[1066] The product was confirmed by LCMS and H-NMR.

[1067] 1 H NMR (400 MHz, CDC13) 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).

[1068] Sixth step

[1069] 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1070] 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1071] 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), and the mixture was reacted at 60 °C for 16 hours in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to obtain a 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).

[1072] The product was confirmed by LCMS, H-NMR and C-NMR.

[1073] 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 = 6.4 Hz), 1.74-1.92 (m, 4H), 1.58-1.73 (m, 4H).

[1074] 13 C 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.

[1075] Example 20: Synthesis of compound T033

[1076] The synthesis route is as follows:

[1077] First step

[1078] 5-(bromomethyl)-2-methoxypyridine

[1079] 5-(bromomethyl)-2-methoxypyridine

[1080] (6-methoxypyridin-3-yl)methanol (0.5 g, 3.6 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and PBr3(1.1 g, 4.0 mmol) was added. The reaction was stirred at room temperature for about 4 hours. After complete reaction, the crude product was directly concentrated under reduced pressure to obtain 5-(bromomethyl)-2-methoxypyridine I152 (1.0 g, crude) as a yellow solid.

[1081] The product was confirmed by LCMS and was directly used in the next step.

[1082] Second step

[1083] methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1084] 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1085] methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1086] The product was confirmed by LCMS and H-NMR.

[1087] 1 H NMR (400 MHz, CDC13) δ: 8.29 (s, 1H), 7.72 (d, 2H, J = 8.4 Hz), 6.79 (d, 2H, J = 8.4 Hz), 5.44 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.49 (s, 3H).

[1088] Third step

[1089] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[1090] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[1091] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[1092] The product was confirmed by LCMS and H-NMR.

[1093] 1 H NMR (400 MHz, CDC13) δ: 8.27 (d, 1H, J = 2.4 Hz), 8.13 (t, 1H, J = 6.0 Hz), 7.71 (dd, 1H, J = 8.4, 2.4 Hz), 7.18 (d, 1H, J = 8.4 Hz), 6.76 (d, 1H, J = 8.4 Hz), 6.44-6.49 (m, 2H), 5.36 (s, 2H), 4.28 (d, 1H, J = 6.4 Hz), 3.96 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H).

[1094] Fourth Step

[1095] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[1096] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[1097] Methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazolium-4-carboxylic acid ester I154 (0.67 g, 1.50 mmol) was dissolved in DCM / H2O (25 / 5 mL). DDQ (1.37 g, 6.02 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After complete reaction, saturated sodium bicarbonate (25 mL) was added to the reaction solution, and the mixture was 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 methyl 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazolium-4-carboxylic acid ester I155 (290 mg, 65.3% yield).

[1098] The product was confirmed by LCMS and H-NMR.

[1099] 1 H NMR (400MHz, 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).

[1100] Step 5

[1101] methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1102] 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidine-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[1103] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (189 mg, 1.33 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (191 mg, 1.33 mmol), stir the reaction at room temperature for 1 h, add DMSO (5 mL), remove most of the THF under reduced pressure, add 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 1155 (280 mg, 0.95 mmol) and potassium carbonate (262 mg, 1.90 mmol), stir the reaction at room temperature for 8 h. After complete reaction, add water (20 mL) to the reaction, extract the mixture with dichloromethane (10 mL x 3), wash the organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure to give the crude product, purify the crude product using preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1156 (230 mg, 52.3% yield) as a yellow solid.

[1104] The product was confirmed by LCMS and H-NMR.

[1105] 1 H NMR (400 MHz, CDC13) δ: 10.30 (br s, 1H), 8.28 (d, 1H, J = 2.0 Hz), 8.01 (br s, 1H), 7.71 (dd, 1H, J = 8.4, 2.4 Hz), 6.76 (d, 1H, J = 8.8 Hz), 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).

[1106] Sixth step

[1107] 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide

[1108] 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide

[1109] In a microwave tube, methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4- (pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I156 (220 mg, 0.47 mmol) was dissolved in NH3 / MeOH (10 mL, 10 mol / L), and the mixture was reacted at 60 °C for 72 h in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to obtain white solid product 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamimidoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide T033 (23 mg, 10.8% yield).

[1110] The product was confirmed by LCMS, H-NMR and C-NMR.

[1111] 1 H NMR (400 MHz, CD3OD) δ: 8.29 (d, 1H, J = 2.4 Hz), 7.86 (dd, 1H, J = 8.4, 2.0 Hz), 6.84 (d, 1H, J = 8.8 Hz), 5.44 (s, 2H), 3.93 (s, 3H), 3.26 (t, 2H, J = 6.8 Hz), 2.69 (s, 4H), 2.62 (t, 2H, J = 7.2 Hz), 1.84-1.88 (m, 4H), 1.59-1.62 (m, 4H).

[1112] 13 C 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.

[1113] Example 21: Synthesis of compound T035

[1114] The synthesis route is as follows:

[1115] First step

[1116] 6-(bromomethyl)-2-methylbenzo[d]oxazole

[1117] 6-(bromomethyl)-2-methylbenzo[d]oxazole

[1118] (2-methyl-1,3-benzoxazol-6-yl)methanol (1 g, 6.1 mmol) was dissolved in DCM (10 mL), cooled to 0 °C, and PBr3(1.66 g, 6.1 mmol) was added. The reaction was stirred at room temperature for about half an hour. After complete reaction, the crude product was directly concentrated under reduced pressure to obtain 6-(bromomethyl)-2-methylbenzo[d]oxazole 1163 (1.1 g, crude) as a yellow solid.

[1119] The product was confirmed by LCMS.

[1120] Second step

[1121] methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1122] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1123] methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1124] The product was confirmed by LCMS and H-NMR.

[1125] 1 H NMR (400 MHz, DMSO-d6) d: 7.79 (s, 1 H), 7.69 (s, 1 H, J = 8.0 Hz), 7.47 (s, 1 H, J = 0.8 Hz), 5.60 (s, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 2.62 (s, 3H).

[1126] Third step

[1127] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1128] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1129] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1130] The product was confirmed by LCMS and H-NMR.

[1131] 1 H NMR (400 MHz, DMSO-d6) δ: 8.41 (t, 1H, J = 6.0 Hz), 7.70 (s, 1H), 7.63 (d, 1H, J = 8.0 Hz), 7.38-7.40 (m, 1H), 7.16 (d, 1H, J = 8.0 Hz), 6.59 (d, 1H, J = 2.4 Hz), 6.50 (dd, 1H, J = 8.0, 2.0 Hz), 5.43 (s, 2H), 4.27 (d, 1H, J = 6.0 Hz), 3.82 (s, 3H), 3.73-3.74 (m, 6H), 2.60 (s, 3H).

[1132] Fourth step

[1133] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1134] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1135] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazol-4-carboxylic acid ester I165 (1 g, 2.13 mmol) was dissolved in DCM / H2O (10 / 2 mL), and DDQ (1.93 g, 8.52 mmol) was added in portions at 0 °C, followed by stirring for 1 hour. After complete reaction, water (100 mL) was added to the reaction solution, and the mixture was 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 methyl 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazol-4-carboxylic acid ester I166 (300 mg, 44.1% yield).

[1136] The product was confirmed by LCMS and H-NMR.

[1137] 1 H NMR(400MHz,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).

[1138] Step 5

[1139] methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1140] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidine-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[1141] Methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate 1166 (300 mg, 0.94 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (30 mL) and saturated brine (30 mL) sequentially, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid product, methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate 1167 (200 mg, 43.7% yield).

[1142] The product was confirmed by LCMS.

[1143] Sixth step

[1144] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide

[1145] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide

[1146] Methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate 1166 (300 mg, 0.94 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (30 mL) and saturated brine (30 mL) sequentially, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid product, methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate 1167 (200 mg, 43.7% yield).

[1147] The product was confirmed by LCMS, H-NMR, and C-NMR.

[1148] 1 H NMR (400 MHz, CDC13) δ: 10.96 (br s, 1H), 7.75 (br s, 1H), 7.68 (d, 1H, J = 8 Hz), 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).

[1149] 13 C NMR (100 MHz, CDC13) 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.

[1150] Example 22: Synthesis of compound T036

[1151] The synthetic route is as follows:

[1152] First step

[1153] 1-(bromomethyl)-4-ethoxybenzene

[1154] 1-(bromomethyl)-4-ethoxybenzene

[1155] (4-ethoxyphenyl)methanol (500 mg, 3.29 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, and PBr3(296 mg, 1.10 mmol) was added. The reaction system was stirred at 10 °C for about 1 hour. After the reaction was completed, the mixture was washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product 1-(bromomethyl)-4-ethoxybenzene 1168 (600 mg, 84.9% yield) as a yellow oily liquid product.

[1156] The product was confirmed by LCMS and H-NMR.

[1157] 1H NMR (400MHz, 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).

[1158] Step 2

[1159] methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1160] 3-((4-ethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid methyl ester

[1161] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylate I009 (500 mg, 2.11 mmol) and potassium carbonate (74 mg, 6.32 mmol) were dissolved in DMF (5 mL). 1-(bromomethyl)-4-ethoxybenzyl 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 solution, and the mixture was filtered to obtain a solid. The filter cake was washed with water and then dried to obtain a crude product, a pale white solid, methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazolium-4-carboxylate I169 (610 mg, 77.9% yield).

[1162] The product was confirmed by LCMS and H-NMR.

[1163] 1 H NMR (400MHz, 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).

[1164] Step 3

[1165] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate

[1166] 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[1167] Methyl 3-((4-ethoxybenzyl)oxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 system was stirred at 65 °C for 1 hour. After the reaction was completed, the reaction solution was added to water (20 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, 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 rapid column chromatography (PE / EA = 10 / 1-5 / 1-3 / 1) to obtain the pale white solid product methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazol-4-carboxylic acid ester I170 (550 mg, 89.1% yield).

[1168] The product was confirmed by LCMS and H-NMR.

[1169] 1 H NMR (400MHz, 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).

[1170] Step 4

[1171] methyl 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate

[1172] 5-Amino-3-((4-ethoxybenzyl)oxy)isothiazol-4-carboxylic acid methyl ester

[1173] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazolium-4-carboxylic acid ester I170 (550 mg, 1.20 mmol) was dissolved in DCM / H2O (1 1 / 2.2 mL). DDQ (817 mg, 3.60 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for 1 hour. After complete reaction, water (40 mL) was added to the reaction solution, the solid was filtered off, 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 methyl 5-amino-3-((4-ethoxybenzyl)oxy)isothiazolium-4-carboxylic acid ester I171 (290 mg, 78.4% yield).

[1174] The product was confirmed by LCMS and H-NMR.

[1175] 1 H NMR (400MHz, 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).

[1176] Step 5

[1177] methyl 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1178] 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[1179] To a solution of 4-(pyrrolidin-l-yl)butan-l -amine (129 mg, 0.91 mmol) in dry THF (5 mL) under N2protection, cool to 0 °C, add CDI (147 mg, 0.91 mmol), stir the reaction at room temperature for 1 h, add DMSO (5 mL), remove most of the THF under reduced pressure, add 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester II 171 (200 mg, 0.65 mmol) and potassium carbonate (179 mg, 1.30 mmol), stir the reaction at room temperature for 1 h. After complete reaction, add water (10 mL) to the reaction, filter to get a solid, wash the filter cake with water, dry to get the crude product as a light white solid product 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester II 172 (180 mg, 58.2% yield).

[1180] The product was confirmed by LCMS and H-NMR.

[1181] 1 H NMR (400 MHz, CDC13) δ: 10.22 (br s, 1H), 8.18 (br s, 1H), 7.41 (d, 2H, J = 8.8 Hz), 6.91 (d, 1H, J = 8.8 Hz), 5.39 (s, 2H), 4.06 (q, 2H, J = 7.2 Hz), 3.96 (s, 3H), 3.33 (d, 2H, J = 5.2 Hz), 2.52-2.64 (m, 6H), 1.89-1.91 (m, 4H), 1.68 (s, 4H), 1.44 (t, 3H, J = 7.2 Hz).

[1182] Sixth step

[1183] 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[1184] 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-l-yl)butyl)ureido)isothiazole-4-carboxamide

[1185] In a microwave tube, methyl 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxylate I172 (100 mg, 0.21 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L), and the mixture was reacted at 60 °C for 16 hours in a sealed tube. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH / NH3.H2O (25%) = 100 / 10 / 1) to obtain a white solid product, 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1- yl)butyl)ureido)isothiazole-4-carboxamide T036 (30 mg, 31.0% yield).

[1186] The product was confirmed by LCMS, H-NMR and C-NMR.

[1187] 1 H NMR (400 MHz, CDCl3) δ: 10.91 (s, 1H), 7.82 (s, 1H), 7.38 (d, 2H, J = 8.8 Hz), 7.18 (s, 1H), 6.92 (d, 2H, J = 8.4 Hz), 5.60 (s, 1H), 5.39 (s, 2H), 4.06 (q, 2H, J = 7.2 Hz), 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 = 7.2 Hz).

[1188] 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.

[1189] Example 23: Synthesis of compound T042

[1190] The synthesis route is as follows:

[1191] First step

[1192] 2,3-dihydrobenzofuran-6-carboxylic acid

[1193] 2,3-dihydrobenzofuran-6-carboxylic acid

[1194] Benzofuran-6-carboxylic acid (4 g, 24.67 mmol) and Pd / C (899 mg) were dissolved in methanol (50 mL) and stirred at room temperature under hydrogen (20 psi) for 16 hours. After the reaction was completed, the mixture was filtered through celite and the filtrate was concentrated under reduced pressure to obtain the crude product as a white solid product 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 91.4% yield).

[1195] The product was confirmed by LCMS and H-NMR.

[1196] 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, 1 H, J = 7.6, 1.6 Hz), 7.32 (d, 1 H, J = 7.6 Hz), 7.23 (d, 1 H, J = 1.2 Hz), 4.57 (t, 2 H, J = 8.8 Hz), 3.23 (t, 2 H, J = 8.8 Hz).

[1197] Second Step

[1198] (2,3-dihydrobenzofuran-6-yl)methanol

[1199] (2,3-dihydrobenzofuran-6-yl)methanol

[1200] Under N2protection, 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 22.54 mmol) was dissolved in anhydrous THF (50 mL) and BH3.Me2S (10 M, 5.63 mL, 56.3 mmol) was added under an ice-water bath. The reaction temperature was raised to 60 °C and stirred for 16 hours. The reaction solution was poured into methanol (100 mL) and concentrated under reduced pressure to obtain the crude product as a colorless liquid product (2,3-dihydrobenzofuran-6-yl)methanol I194 (3.3 g, 97.49% yield).

[1201] The product was confirmed by LCMS and directly used in the next step.

[1202] Third Step

[1203] 6-(bromomethyl)-2,3-dihydrobenzofuran

[1204] 6-(bromomethyl)-2,3-dihydrobenzofuran

[1205] (2,3-Dihydrobenzofuran-6-yl)methanol I194 (3.3 g, 21.97 mmol) was dissolved in DCM (50 mL), cooled to 0 °C, and PBr3 (8.92 g, 32.96 mmol) was added. The reaction mixture was stirred at room temperature for about 1 hour. After complete reaction, the mixture was added to a cold saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (4 g, 85.3% yield) as a white product.

[1206] The product has been verified by LCMS.

[1207] Step 4

[1208] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1209] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[1210] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylate I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMF (10 mL). 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (0.99 g, 4.64 mmol) 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 (20 mL x 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 rapid column chromatography (PE / EA = 10 / 1) to obtain the white solid product methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazolium-4-carboxylate I196 (1.2 g, 77.1% yield).

[1211] The product was confirmed by LCMS and H-NMR.

[1212] 1H NMR (400MHz, 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).

[1213] Step 5

[1214] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1215] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[1216] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methanesulfonyl)isothiazol-4-carboxylic acid 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 the reaction was completed, the reaction solution was added to ice water (30 mL), the pH was adjusted to 5, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (20 mL) and saturated brine (20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid product, methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid ester I197 (1.3 g, 75.1% yield).

[1217] The product was confirmed by LCMS and H-NMR.

[1218] 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).

[1219] Step 6

[1220] methyl 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylate

[1221] 5-Amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[1222] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester I197 (1.64 g, 3.59 mmol) was dissolved in DCM / H2O (15 / 3 mL), and DDQ (1.22 g, 5.39 mmol) was added in portions at 0 °C. The reaction system was stirred at room temperature for 20 minutes. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was 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 using a chromatography column (PE / EA = 10 / 1-3 / 1) to obtain the yellow solid product methyl 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazol-4-carboxylic acid ester I198 (0.4 g, 36.4% yield).

[1223] The product has been verified by LCMS.

[1224] Step 7

[1225] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1226] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidone-1-yl)butyl)ureo)isothiazol-4-carboxylic acid methyl ester

[1227] To a solution of 4-(pyrrolidin-1-yl)butan-1 -amine (390 mg, 2.74 mmol) in dry THF (10 mL) under N2protection, cool to 0 °C, add CDI (445 mg, 2.74 mmol), stir the reaction at room temperature for 1 h, add DMSO (10 mL), remove most of the THF under reduced pressure, add 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester 1198 (0.6 g, 1.96 mmol) and potassium carbonate (541 mg, 3.92 mmol), stir the reaction at room temperature for 16 h. After complete reaction, add water (40 mL) to the reaction, extract the mixture with ethyl acetate (20 mL x 3), wash the organic phase with water (30 mL) and saturated brine (30 mL) successively, dry over anhydrous sodium sulfate and concentrate under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1199 (0.6 g, 64.6% yield) as a yellow solid.

[1228] The product is confirmed by LCMS.

[1229] Eighth step

[1230] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1231] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1232] In a microwave tube, dissolve 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester 1199 (400 mg, 0.84 mmol) in NH3 / MeOH (20 mL, 9 mol / L), stir the mixture at 60 °C for 16 h. Concentrate the reaction under reduced pressure to give the crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T042 (15 mg, 3.87% yield) as a white solid.

[1233] The product was confirmed by LCMS, H-NMR and C-NMR.

[1234] 1 H NMR (400 MHz, CDC13) δ: 11.67 (br s, 1H), 11.10 (s, 1H), 7.37 (s, 1H), 7.21 (d, 1H, J = 6.4 Hz), 6.92 (d, 1H, J = 7.6 Hz), 6.87 (s, 1H), 6.14 (br s, 1H), 5.38 (s, 2H), 4.61 (t, 2H, J = 8.8 Hz), 3.79 (s, 2H), 3.37-3.38 (m, 2H), 3.23 (t, 2H, J = 8.8 Hz), 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).

[1235] 13 C 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.

[1236] Example 24: Synthesis of compound T044

[1237] The synthetic route is as follows:

[1238] First step

[1239] 5-(bromomethyl)-2,3-dihydrobenzofuran

[1240] 5-(bromomethyl)-2,3-dihydrobenzofuran

[1241] 5-(bromomethyl)-2,3-dihydrobenzofuran

[1242] The product has been verified by LCMS.

[1243] Step 2

[1244] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1245] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid methyl ester

[1246] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazolium-4-carboxylate I009 (0.5 g, 2.11 mmol) and potassium carbonate (0.58 g, 4.21 mmol) were dissolved in DMF (5 mL). 5-(bromomethyl)-2,3-dihydrobenzofuran I203 (494 mg, 2.32 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted separately with ethyl acetate (20 mL x 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 rapid column chromatography (PE / EA = 10 / 1) to obtain the white solid product methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazolium-4-carboxylate I204 (0.5 g, 64.2% yield).

[1247] The product was confirmed by LCMS and H-NMR.

[1248] 1 H NMR (400MHz, CDCl3): δ (ppm) 7.32 (s, 1H), 7.23 (d, 1H, J = 7.6Hz), 6.79 (d, 1H, J = 8.0 Hz),5.41(s,2H),4.58-4.63(m,2H),3.95(s,3H),3.47(s,3H),3.22-3.26(m,2H).

[1249] Step 3

[1250] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1251] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazol-4-carboxylic acid methyl ester

[1252] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methanesulfonyl)isothiazolium-4-carboxylic acid 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 the reaction was completed, the reaction solution was added to ice water (10 mL), the pH was adjusted to 5, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid product, methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylic acid ester I205 (0.19 g, 76.9% yield).

[1253] The product has been verified by LCMS.

[1254] Step 4

[1255] methyl 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylate

[1256] 5-Amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazol-4-carboxylic acid methyl ester

[1257] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazolium-4-carboxylate I205 (683 mg, 1.50 mmol) was dissolved in DCM / H2O (5 / 1 mL). DDQ (509 mg, 2.24 mmol) was added in portions at 0 °C, and the reaction mixture was stirred at room temperature for half an hour. After complete reaction, the mixture was filtered, and the filtrate was added to water (10 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified using a chromatography column (PE / EA = 10 / 1 to 3 / 1) to obtain the yellow solid product methyl 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazolium-4-carboxylate I206 (0.1 g, 21.8% yield).

[1258] The product has been verified by LCMS.

[1259] Step 5

[1260] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1261] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1262] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate was prepared according to the procedure described above for the preparation of methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(piperidin-1-yl)butyl)ureido)isothiazole-4-carboxylate, using 4-(pyrrolidin-1-yl)butan-1-amine (65. mg, 0.46 mmol) instead of 4-(piperidin-1-yl)butan-1-amine. The product was confirmed by LCMS.

[1263] The product was confirmed by LCMS.

[1264] Sixth step

[1265] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1266] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1267] In a microwave tube, methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4- (pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I207 (0.25 g, 0.53 mmol) was dissolved in NH3 / MeOH (6 mL, 9 mol / L), and the mixture was stirred at 65 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified using preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to obtain a 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).

[1268] The product was confirmed by LCMS, H-NMR and C-NMR.

[1269] 1 H NMR (400 MHz, CDC13): δ (ppm) 11.07 (s, 1H), 7.44-7.47 (m, 1H), 7.28-7.30 (m, 1H), 7.16-7.22 (m, 2H), 6.80 (d, 1H, J = 8.4 Hz), 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).

[1270] 13 C NMR (100 MHz, CDC13) 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

[1271] Example 25: Synthesis of compound T045

[1272] The synthesis route is as follows:

[1273] First step

[1274] 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine

[1275] 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine

[1276] 5-bromo-pyridin-3-ol (1.5 g, 8.62 mmol) was dissolved in DMF (15.0 mL), 1-(2-chloroethyl)pyrrolidine hydrochloride (1.76 g, 10.35 mmol) and sodium hydroxide (1.38 g, 34.48 mmol) were added, the reaction system was raised to 70 °C and stirred for 2 hours. The reaction liquid was poured into water (60 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography to obtain the product 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine I208 (1.6 g, 68.5% yield) as a yellow oily liquid.

[1277] The product was confirmed by LCMS.

[1278] Second step

[1279] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine

[1280] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine

[1281] 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine I208 (1 g, 3.69 mmol) was dissolved in NMP (10 mL), 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 hours. After complete reaction, the insoluble material was filtered off with diatomite, the filtrate was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (DCM / MeOH = 120 / 1-40 / 1, 0.1% NH3·H2O) to obtain the product 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine I209 (0.6 g, 78.5% yield) as a yellow solid.

[1282] The product was confirmed by LCMS.

[1283] Third step

[1284] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylate

[1285] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide

[1286] Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylate I178 (0.9 g, 2.04 mmol) was dissolved in THF (30 mL), 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 reaction was stirred at 30 °C for 5 hours. After the reaction was completed, the mixture was poured into water (50 mL), extracted with ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (DCM / MeOH = 150 / 1-120 / 1) to obtain the 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) as a yellow oily liquid.

[1287] The product was confirmed by LCMS.

[1288] Fourth step

[1289] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide

[1290] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide

[1291] In a microwave tube, methyl 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2- (pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylate I210 (0.36 g, 0.63 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L), and the mixture was stirred at 65 °C for 16 h. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give 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).

[1292] The product was confirmed by LCMS, H-NMR and C-NMR.

[1293] 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 = 5.6 Hz), 2.85 (s, 2H), 2.57 (m, 4H), 1.70 (s, 4H).

[1294] 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.

[1295] Example 26: Synthesis of compound T046

[1296] The synthesis route is as follows:

[1297] First step

[1298] tert-butyl 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1299] 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate tert-butyl

[1300] tert-butyl 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1301] The product was confirmed by LCMS.

[1302] Second step

[1303] tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1304] tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1305] tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1306] The product was confirmed by LCMS and H-NMR.

[1307] 1 H NMR (400 MHz, CDCl3) δ: 7.17 (s, 1H), 7.10 (s, 1H), 4.14 (t, 2H, J = 6.4 Hz), 3.43 (t, 4H, J = 4.8 Hz), 2.79 (t, 1H, J = 6.4 Hz), 2.42 (s, 4H), 1.47 (s, 9H).

[1308] Third step

[1309] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-

[1310] 4-yl)amino)isothiazole-4-carboxylate

[1311] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-4-yl)amino)isothiazol-4-carboxylic acid methyl ester

[1312] Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazolyl-4-carboxylic acid 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 then stirred and reacted for about 1 hour. After complete reaction, water (30 mL) and ethyl acetate (30 mL x 3) were added to the mixture for extraction. 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 high performance preparative chromatography to obtain the white solid product methyl 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-4-yl)amino)isothiazolium-4-carboxylic acid I213 (10 mg, 2.2% yield).

[1313] The product was identified by LCMS and H-NMR.

[1314] 1 H NMR (400MHz, 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).

[1315] Step 4

[1316] 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

[1317] 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

[1318] Methyl 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxylate I213 (160 mg, 0.24 mmol) was dissolved in NH3 / MeOH (5 mL, 9 mol / L) in a microwave tube, and the mixture was stirred at 70 °C for 48 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give tert-butyl 4-(2-(4-((3-((4-bromo-2,6-difluorophenyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate T046 (7 mg, 4.4% yield) as a white solid.

[1319] The product was confirmed by LCMS and H-NMR.

[1320] 1 H NMR (400 MHz, CDC13) δ: 10.09 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.19 (d, 2H, J = 6.8 Hz), 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).

[1321] Example 27: Synthesis of compound T049

[1322] The synthesis route is as follows:

[1323] First step

[1324] N,3-dimethylbenzamide

[1325] N,3-dimethylbenzamide

[1326] N,3-dimethylbenzamide (5 g, 36.72 mmol) was dissolved in anhydrous DMF (50 mL), methylamine hydrochloride (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, then the reaction was stirred for 3 hours. After the reaction was completed, the mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA = 3 / 1-1 / 1) to obtain the product N,3-dimethylbenzamide I218 (4.8 g, 87.6% yield) as a yellow oily liquid.

[1327] The product was confirmed by LCMS and H-NMR.

[1328] 1 H 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 = 4.4 Hz), 2.41 (s, 3H).

[1329] Second step

[1330] 3-(bromomethyl)-N-methylbenzamide

[1331] 3-(bromomethyl)-N-methylbenzamide

[1332] N,3-dimethylbenzamide I218 (4 g, 26.81 mmol) was dissolved in CCl4(80 mL), AIBN (440 mg, 2.68 mmol) and NBS (5.73 g, 32.17 mmol) were added at room temperature, and the reaction was stirred at 80°C under reflux for 16 hours. After the reaction was completed, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA = 10 / 1-5 / 1-1 / 1) to obtain the product 3-(bromomethyl)-N-methylbenzamide I219 (4.6 g, crude) as a brownish yellow oily liquid.

[1333] Third step

[1334] methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1335] methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1336] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (2 g, 8.43 mmol) and potassium carbonate (3.5 g, 25.29 mmol) were dissolved in DMF (40 mL), 3-(bromomethyl)-N-methylbenzamide I219 (4.61 g, 10.12 mmol) was added, the reaction system was stirred at room temperature for 1 hour. Water (200 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50 mL x 3), the organic phase was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, 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 obtain white solid product methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I220 (2.4 g, 74.06% yield).

[1337] The product was confirmed by LCMS and H-NMR.

[1338] 1 H NMR (400 MHz, CDC13) δ: 7.93 (s, 1H), 7.72 (d, 1H, J = 7.6 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.47 (t, 1H, J = 8.0 Hz), 6.23 (s, 1H), 5.54 (s, 2H), 4.00 (s, 3H), 3.50 (s, 3H), 3.05 (d, 3H, J = 5.2 Hz).

[1339] Fourth step

[1340] methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate

[1341] methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate

[1342] Methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazol-4-carboxylic acid 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 the reaction was completed, the reaction solution was added to water (100 mL), and the mixture w...

Claims

An ophthalmic preparation comprising: a. A compound or a pharmaceutically acceptable salt thereof; b. Potential solvent; c. Pharmaceutically acceptable excipients; in, The pharmaceutically acceptable excipients include one or more combinations of solubilizers, viscosity modifiers, and buffers. The compound has the following structure: in, Ring A is a 5-7 membered heteroaryal ring; Ring B is C6-C 10 Aromatic rings or 5-10-membered heterocyclic rings; optionally, the C6-C 10 Aromatic rings or 5-10 membered heterocycles can interact with C6-C 10 Aromatic rings, C5-C8 aliphatic rings, and 5-10 membered heterocyclic rings are fused together; X1 is either O or S; Y is -N(C0-C) 10 Alkyl) (C0-C 10 alkyl) or -O (C0-C) 10 alkyl); L1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)NR3-, -C(O)N(R3)O-, -S(O)2-, -S(O)2NR3-, -S(O)-, -S(O)NR3-, -Cy-; -Cy- is selected from: substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heterocyclic alkylene; L2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following: -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; where a and b are independently selected from integers from 0 to 10, R L201 and R L202 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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, cycloalkylalkyl, heterocyclic, heterocyclic alkyl; wherein, R L203 and R L204 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl; L3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following: -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; where c and d are independently selected from integers from 0 to 10, R L301 and R L302 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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, cycloalkylalkyl, heterocyclic, heterocyclic alkyl; wherein, R L303 and R L304 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl; Each of R3 to R5 is independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted by a group selected from: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; R1 is one or more independent substituents on ring B, each R1 being independently selected from: H, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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), -SO2(CH2) t (C6-C 10 Aryl), -S(CH2) t (C6-C 10 Aryl), -O(CH2) t (C6-C 10 Aryl), -(CH2) t (4-10 membered heterocyclic group), -SO2(CH2) t (4-10 membered heterocyclic group), -S(CH2) t (4-10 membered heterocyclic group), -O(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl groups), -SO2(CH2) t (C3-C 10 cycloalkyl), -S(CH2) t (C3-C 10 cycloalkyl), -O(CH2) t (C3-C 10 cycloalkyl), where t is an integer from 0 to 5; wherein, the C1-C 10 Alkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups are optionally substituted with groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; Each R 101 To R 104 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if the valence allows); R0 is selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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 Where i is an integer from 0 to 2, -SO3H, -NR 002 (CR 003 R 004 ) t OR 001 , Among them, ring E is C6-C 10 Aromatic rings or 4-10-membered heterocyclic rings; optionally, the C6-C 10 Aromatic rings or 4-10 membered heterocycles can interact with C6-C 10 Aromatic rings, C5-C8 aliphatic rings, and 4-10 membered heterocyclic rings are fused together; R2 is selected from: H, =O, Cl-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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), -SO2(CH2) j (C6-C 10 Aryl), -S(CH2) j (C6-C 10 Aryl), -O(CH2) j (C6-C 10 Aryl), -(CH2) j (4-10 membered heterocyclic group), -SO2(CH2) j (4-10 membered heterocyclic group), -S(CH2) j (4-10 membered heterocyclic group), -O(CH2) j (4-10 membered heterocyclic group), -(CH2) j (C3-C 10 cycloalkyl groups), -SO2(CH2) j (C3-C 10 cycloalkyl), -S(CH2) j (C3-C 10 cycloalkyl), -O(CH2) j (C3-C 10 cycloalkyl), where j is an integer from 0 to 5; wherein, the C1-C 10 Alkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups are optionally substituted with groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if the valence allows); Each R 001 To R 004 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; Each R 201 To R 204 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; R' and R" are independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl. The ophthalmic preparation as described in claim 1, characterized in that, The concentration of the compound in ophthalmic formulation I is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml), preferably from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml). The ophthalmic formulation as described in claim 1 or 2 is characterized in that, The co-solvent is selected from: polyethylene glycol (especially liquid polyethylene glycol, such as polyethylene glycol 200, 300, 400), propylene glycol, glycerin, diethylene glycol monoethyl ether; preferably polyethylene glycol 400; and / or, The concentration of the co-solvent is from 1% v / v to 10% v / v, preferably from 1% v / v to 5% v / v. The ophthalmic formulation according to any one of claims 1-3 is characterized in that, The solubilizer is a cyclodextrin, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, ethyl-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfonyl butyl ether-β-cyclodextrin, branched-chain-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or combinations thereof, preferably hydroxypropyl-β-cyclodextrin, sulfonyl butyl ether-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, or combinations thereof; and / or, The concentration of the solubilizer is from 1% w / v to 30% w / v, preferably from 5% w / v to 20% w / v. The ophthalmic preparation according to any one of claims 1-4 is characterized in that, The viscosity modifier is selected from: cellulose derivatives (e.g., carboxymethyl cellulose, hydroxyethyl cellulose), carbomer, gellan gum, chitosan or its derivatives, xanthan gum, hyaluronic acid or its salts (e.g., sodium hyaluronate), alginate or its salts (e.g., sodium alginate), poloxamer series, polyvinyl alcohol, polyvinylpyrrolidone or combinations thereof. Preferably, the viscosity modifier is poloxamer 188, with a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifier is gellan gum, with a concentration of 0.01% w / v to 5% w / v, preferably 0.1% w / v to 0.5% w / v; or, The viscosity modifier is carbomer, with a concentration of 0.01% w / v to 1% w / v, preferably 0.1% w / v to 0.6% w / v; or, The viscosity modifier is poloxamer 188 and gellan gum, with a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifiers are poloxamer 188 and carbomer, with concentrations ranging from 0.01% w / v to 5% w / v. The ophthalmic formulation according to any one of claims 1-5 is characterized in that, The buffer comprises: tromethamine, histidine, carnosine, phosphate, or a combination thereof; Preferably, the buffer is tromethamine-hydrochloric acid buffer. The ophthalmic formulation according to any one of claims 1-6 is characterized in that, The pharmaceutically acceptable excipients also include surfactants; Preferably, the surfactant is selected from: polyoxyethylene castor oil, tylosap, Tween, polyoxyethylene 40 hydrogenated castor oil, or a combination thereof; More preferably, the surfactant is polyoxyethylene castor oil or tylosap; Preferably, the concentration of the surfactant is from 0.1% w / v to 10% w / v, more preferably from 0.5% w / v to 2% w / v. The ophthalmic formulation according to any one of claims 1-7 is characterized in that, The pharmaceutically acceptable excipients also include one or more of the following: pH adjusters, osmotic pressure regulators, preservatives, and solvents. The ophthalmic preparation as described in claim 1, characterized in that, The ophthalmic preparation comprises: a. The compound or a pharmaceutically acceptable salt thereof; b. Polyethylene glycol 400; c. Hydroxypropyl-β-cyclodextrin, poloxamer 188, gellan gum, tromethamine-hydrochloride buffer, deionized water; or, The ophthalmic preparation comprises: a. The compound or a pharmaceutically acceptable salt thereof; b. Polyethylene glycol 400; c. Hydroxypropyl-β-cyclodextrin, poloxamer 188, carbomer, tromethamine-hydrochloride buffer, deionized water. The ophthalmic preparation according to any one of claims 1-9 is characterized in that, The ophthalmic preparation is a homogeneous preparation, such as a solution, emulsion, suspension, gel, especially a solution; Preferably, the pH of the ophthalmic preparation is 5 to 9, more preferably 6 to 8; Preferably, the osmotic pressure of the ophthalmic preparation is from 200 mOsm / kg to 500 mOsm / kg, and more preferably from 250 mOsm / kg to 450 mOsm / kg. The method for preparing the ophthalmic formulation according to any one of claims 1-10 comprises the following steps: (1) Disperse the compound or its pharmaceutically acceptable salt in a coagulant; (2) Add the mixture obtained in step (1) to the pharmaceutically acceptable excipients and mix; Preferably, step (2) includes: Add the mixture obtained in step (1) to a buffer containing solubilizer, surfactant and viscosity modifier, and mix. An ophthalmic preparation, the raw materials of which include: a. A compound or a pharmaceutically acceptable salt thereof; b. Pharmaceutically acceptable excipients; c. Alkaline pH adjusters; in, The pharmaceutically acceptable excipients include: solubilizers, surfactants, and viscosity modifiers; The compound has the following structure: in, Ring A is a 5-7 membered heteroaryal ring; Ring B is C6-C 10 Aromatic rings or 5-10-membered heterocyclic rings; optionally, the C6-C 10 Aromatic rings or 5-10 membered heterocycles can interact with C6-C 10 Aromatic rings, C5-C8 aliphatic rings, and 5-10 membered heterocyclic rings are fused together; X1 is either O or S; Y is -N(C0-C) 10 Alkyl) (C0-C 10 alkyl) or -O (C0-C) 10 alkyl); L1 is selected from: single bond, -C(O)-, -C(O)O-, -C(O)NR3-, -C(O)N(R3)O-, -S(O)2-, -S(O)2NR3-, -S(O)-, -S(O)NR3-, -Cy-; -Cy- is selected from: substituted or unsubstituted cycloalkylene, substituted or unsubstituted arylene, substituted or unsubstituted heterocyclic alkylene; L2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following: -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; where a and b are independently selected from integers from 0 to 10, R L201 and R L202 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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, cycloalkylalkyl, heterocyclic, heterocyclic alkyl; wherein, R L203 and R L204 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl; L3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following: -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; where c and d are independently selected from integers from 0 to 10, R L301 and R L302 Independently selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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, cycloalkylalkyl, heterocyclic, heterocyclic alkyl; wherein, R L303 and R L304 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl; Each of R3 to R5 is independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted by a group selected from: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; R1 is one or more independent substituents on ring B, each R1 being independently selected from: H, C1-C. 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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), -SO2(CH2) t (C6-C 10 Aryl), -S(CH2) t (C6-C 10 Aryl), -O(CH2) t (C6-C 10 Aryl), -(CH2) t (4-10 membered heterocyclic group), -SO2(CH2) t (4-10 membered heterocyclic group), -S(CH2) t (4-10 membered heterocyclic group), -O(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl groups), -SO2(CH2) t (C3-C 10 cycloalkyl), -S(CH2) t (C3-C 10 cycloalkyl), -O(CH2) t (C3-C 10 cycloalkyl), where t is an integer from 0 to 5; wherein, the C1-C 10 Alkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups are optionally substituted with groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; Each R 101 To R 104 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group; wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if the valence allows); R0 is selected from: H, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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 Where i is an integer from 0 to 2, -SO3H, -NR 002 (CR 003 R 004 ) t OR 001 , Among them, ring E is C6-C 10 Aromatic rings or 4-10-membered heterocyclic rings; optionally, the C6-C 10 Aromatic rings or 4-10 membered heterocycles can interact with C6-C 10 Aromatic rings, C5-C8 aliphatic rings, and 4-10 membered heterocyclic rings are fused together; R2 is selected from: H, =O, Cl-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 Alkyne, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, -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), -SO2(CH2) j (C6-C 10 Aryl), -S(CH2) j (C6-C 10 Aryl), -O(CH2) j (C6-C 10 Aryl), -(CH2) j (4-10 membered heterocyclic group), -SO2(CH2) j (4-10 membered heterocyclic group), -S(CH2) j (4-10 membered heterocyclic group), -O(CH2) j (4-10 membered heterocyclic group), -(CH2) j (C3-C 10 cycloalkyl groups), -SO2(CH2) j (C3-C 10 cycloalkyl), -S(CH2) j (C3-C 10 cycloalkyl), -O(CH2) j (C3-C 10 cycloalkyl), where j is an integer from 0 to 5; wherein, the C1-C 10 Alkyl, C6-C 10 The aryl and 4-10 membered heterocyclic groups are optionally substituted with groups selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if the valence allows); Each R 001 To R 004 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; Each R 201 To R 204 Independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl, C1-C 10 Silyl group, wherein the alkyl, cycloalkyl, or heterocyclic group is optionally substituted with a group selected from the following: halogen, cyano, nitro, azide, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR”, -NR'SO2R”, -SO2NR'R”, -NR'C(O)R”, -C(O)NR'R”, -NR'R”, -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Silyl, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic groups; R' and R" are independently selected from: H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic alkyl. The ophthalmic formulation as described in claim 12, characterized in that, The concentration of the compound is from 0.01% w / v (0.1 mg / ml) to 5% w / v (50 mg / ml), preferably from 0.1% w / v (1 mg / ml) to 2.0% w / v (20 mg / ml). The ophthalmic formulation as described in claim 12 or 13 is characterized in that, The solubilizer is a cyclodextrin, such as hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, ethyl-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin, sulfonyl butyl ether-β-cyclodextrin, branched-chain-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, trimethyl-γ-cyclodextrin, or combinations thereof, preferably hydroxypropyl-β-cyclodextrin, sulfonyl butyl ether-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, or combinations thereof; and / or, The concentration of the solubilizer is from 1% w / v to 30% w / v. The ophthalmic formulation according to any one of claims 12-14 is characterized in that, The viscosity modifier is selected from: cellulose derivatives (e.g., carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose), carbomer, gellan gum, chitosan or its derivatives, xanthan gum, hyaluronic acid or its salts (e.g., sodium hyaluronate), alginate or its salts (e.g., sodium alginate), poloxamer series, polyvinyl alcohol, polyvinylpyrrolidone or combinations thereof. Preferably, the viscosity modifier is poloxamer 188, with a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifier is gellan gum, with a concentration of 0.01% w / v to 5% w / v, preferably 0.1% w / v to 0.5% w / v; or, The viscosity modifier is carbomer, with a concentration of 0.01% w / v to 1% w / v, preferably 0.1% w / v to 0.6% w / v; or, The viscosity modifier is poloxamer 188 and gellan gum, with a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifier is poloxamer 188 and carbomer, at a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifier is sodium hyaluronate, with a concentration of 0.01% w / v to 5% w / v; or, The viscosity modifier is hydroxypropyl methylcellulose, with a concentration of 0.01% w / v to 5% w / v. The ophthalmic formulation according to any one of claims 12-15 is characterized in that, The surfactant is selected from: polyoxyethylene castor oil, tyloxapine, Tween, polyoxyethylene 40 hydrogenated castor oil or combinations thereof, preferably polyoxyethylene castor oil or tyloxapine. Preferably, the concentration of the surfactant is from 0.1% w / v to 10% w / v, and more preferably from 0.5% w / v to 5% w / v. The ophthalmic formulation according to any one of claims 12-16 is characterized in that, The alkaline pH adjuster is selected from sodium hydroxide and tromethamine, preferably tromethamine. The ophthalmic formulation according to any one of claims 12-17 is characterized in that, The a is a compound, and the raw materials for preparation further include: d. an acidic pH adjuster; Preferably, the acidic pH adjuster is selected from: aspartic acid, glutamic acid, malonic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, benzoic acid, propionic acid, acetic acid, decanoic acid, stearic acid, oleic acid, hexanoic acid, adipic acid, caprylic acid, tartaric acid, citric acid, malic acid, gluconic acid, glycolic acid, lactic acid, hydrobromic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, and preferably from: methanesulfonic acid, citric acid, and succinic acid. The ophthalmic formulation according to any one of claims 12-18 is characterized in that, The pharmaceutically acceptable excipients also include buffers; Preferably, the buffer comprises: tromethamine, histidine, carnosine, phosphate, or a combination thereof; More preferably, the buffer is tromethamine-hydrochloric acid buffer. The ophthalmic formulation according to any one of claims 12-19 is characterized in that, The pharmaceutically acceptable excipients also include one or more of the following: osmotic pressure regulators, preservatives, and solvents. The ophthalmic formulation as described in claim 12, characterized in that, The raw materials for preparing the ophthalmic formulation include: a. The compound; b. Hydroxypropyl-β-cyclodextrin, polyoxyethylene castor oil, poloxamer 188, gellan gum, tromethorphan-hydrochloric acid buffer, deionized water; c. Tromethamine; d. Succinic acid; or, The raw materials for preparation include: a. The compound; b. Hydroxypropyl-β-cyclodextrin, tyloxapine, gellan gum, tromethamine-hydrochloride buffer, deionized water; c. Tromethamine; d. Citric acid; or, The raw materials for preparation include: a. A pharmaceutically acceptable salt of the compound; b. Hydroxypropyl-β-cyclodextrin, polyoxyethylene castor oil, gellan gum, glycerin, deionized water; c. Tromethamine; or, The raw materials for preparation include: a. The compound or a pharmaceutically acceptable salt thereof; b. Tyloxapine, hydroxypropyl-β-cyclodextrin, glycerol, deionized water; c. Tromethamine; or, The raw materials for preparation include: a. The compound or a pharmaceutically acceptable salt thereof; b. Tyloxapine, hydroxypropyl-β-cyclodextrin, hydroxypropyl methylcellulose, glycerol, deionized water; c. Tromethamine; or, The raw materials for preparation include: a. The compound or a pharmaceutically acceptable salt thereof; b. Tyloxapine, hydroxypropyl-β-cyclodextrin, sodium hyaluronate, glycerin, deionized water; c. Tromethamine. The ophthalmic formulation according to any one of claims 12-21 is characterized in that, The ophthalmic preparation is a homogeneous preparation, such as a solution, emulsion, suspension, gel, especially a solution; Preferably, the pH of the ophthalmic preparation is 5 to 9, more preferably 6 to 8; Preferably, the osmotic pressure of the ophthalmic preparation is from 200 mOsm / kg to 500 mOsm / kg, and more preferably from 250 mOsm / kg to 450 mOsm / kg. The method for preparing the ophthalmic formulation according to any one of claims 12-22 comprises the following steps: (1) The compound is added to a solution containing a portion of pharmaceutically acceptable excipients and dispersed; (2) Add an acidic pH adjuster and mix; (3) Add the remaining pharmaceutically acceptable excipients and mix; (4) Add an alkaline pH adjuster; The pharmaceutically acceptable excipients mentioned in step (1) are solubilizers and surfactants; Preferably, the amount of acidic pH adjuster added in step (2) is to adjust the pH to 3-5; Preferably, step (3) involves adding a buffer containing a viscosity modifier and mixing. Preferably, the amount of alkaline pH adjuster added in step (4) is to adjust the pH to 5 to 9, especially 6 to 8; Alternatively, the preparation method may include the following steps: (A) Disperse a pharmaceutically acceptable salt of the compound in a solution containing a pharmaceutically acceptable excipient; (B) Add an alkaline pH adjuster; The pharmaceutically acceptable excipients mentioned in step (A) include solubilizers, surfactants, and viscosity modifiers; Preferably, the amount of alkaline pH adjuster added in step (B) is to adjust the pH to 5 to 9, particularly 6 to 8. The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, Ring A is in particular Preferably, Some have the following structure: in particular The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, Ring B can be a benzene ring, a benzo[aliphatic] ring, or a heterocycle; Preferably, ring B is selected from: More preferably, Some are selected from the following structure: The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, Each R1 is independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, cyano, nitro, azide, -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), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), where t is an integer from 0 to 5; Preferably, R 101 and R 102 Independently selected from: H, C1-C6 alkyl groups (e.g., -CH3, ... C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 hydroxysubstituted alkyl groups (e.g.) ), C1-C6 alkoxy-substituted alkyl groups (e.g. ), C1-C6 amino-substituted alkyl groups (e.g. ), C1-C6 alkylamine substituted alkyl groups (e.g. C3-C 10 cycloalkyl (e.g.) C4-C 10 Cycloalkylalkyl (e.g.) ), substituted or unsubstituted 4-10 membered heterocyclic groups (e.g. C1-C 10 Silyl-substituted alkyl (e.g.) C1-C 10 Silyl (e.g.) )； More preferably, each R1 is independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azide, -OH The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, R0 is E rings are 4-10 membered heterocycles, especially 4-8 membered saturated heterocycles; Preferably, ring E is selected from: More preferably, Part of The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, R2 is selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, halogen, cyano, nitro, azide, -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), -(CH2) j (4-10 membered heterocyclic group), -(CH2) j (C3-C 10 cycloalkyl), where j is an integer from 0 to 5; Preferably, R 201 and R 202 Independently selected from: H, C1-C6 alkyl groups (e.g., -CH3, ... C1-C6 haloalkyl groups (e.g., -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C1-C6 hydroxysubstituted alkyl groups (e.g.) ), C1-C6 alkoxy-substituted alkyl groups (e.g. ), C1-C6 amino-substituted alkyl groups (e.g. ), C1-C6 alkylamine substituted alkyl groups (e.g. C3-C 10 cycloalkyl (e.g.) C4-C 10 Cycloalkylalkyl (e.g.) ), substituted or unsubstituted 4-10 membered heterocyclic groups (e.g. More preferably, R2 is selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azide, hydroxyl, methoxy, ethoxy More preferably, R0 is selected from: The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, R0 is -NR 001 R 002 , where R 001 and R 002 Independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy-substituted alkyl, C1-C6 alkoxy-substituted alkyl, C1-C6 amino-substituted alkyl, C1-C6 alkylamino-substituted alkyl, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, R0 is selected from: or, R0 is selected from: H, cyano, -O(CO-C) 10 Alkyl), -O(C1-C) 10 silyl), -S(CO-C) 10 Alkyl), -C(O)(C0-C 10 Alkyl), -C(O)O(C0-C) 10 Alkyl), -OC(O)(C0-C 10 Alkyl), -N(C0-C) 10 Alkyl)SO2(C0-C 10 Alkyl), -SO2N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -N(C0-C) 10 alkyl)C(O)(C0-C 10 Alkyl), -C(O)N(C0-C) 10 Alkyl) (C0-C 10 Alkyl), -SO2(C0-C) 10 Alkyl group, wherein the alkyl group is optionally substituted with a group selected from the following groups: halogen, cyano, hydroxyl, amino, C1-C6 alkoxy, C1-C6 alkylamine, C3-C6 cycloalkyl. Preferably, R0 is selected from: H, cyano, -OH, -COOH、 The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, L1 is -C(O)NH-, -Cy-, a single bond, or -C(O)-; Preferably, -Cy- is selected from: Each R 10 Independently selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy-substituted alkyl, C1-C6 alkylamino-substituted alkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl, 4-10 membered heterocyclic groups; More preferably, -Cy- is selected from: The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, L2 is a single bond or C2-C 10 Alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted with groups selected from the following groups: -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 one or more H atoms in the alkylene are optionally and independently substituted with the following groups: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, L2 is a C2-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted by groups selected from the following: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-; More preferably, L2 is selected from: single bonds, The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, L3 is a C1-C6 alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted with groups selected from the following: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, wherein one or more H atoms in the alkylene group are optionally and independently substituted with groups selected from the following: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azide, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, L3 is a methylene group. The ophthalmic preparation according to any one of claims 1-10 and 12-22 is characterized in that, The compound is selected from: The use of the ophthalmic formulation as described in any one of claims 1-10, 12-22, 24-33 in the preparation of a medicament for the prevention and / or treatment of protein tyrosine kinase-mediated proliferative diseases; The diseases described are ocular diseases, preferably from: diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy, and diabetic macular edema); age-related macular degeneration (including neovascular (wet / exudative) age-related macular degeneration, dry age-related macular degeneration, and geographic atrophy); pathological choroidal neovascularization (i.e., high myopia, trauma, sickle cell (anemia) disease; ocular histoplasmosis, angiostriate syndrome, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophys); pathological retinal neovascularization. (i.e., sickle cell retinopathy, Ilse disease, ocular ischemia syndrome, carotid-cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteritis, guanomorphic choroidal disease, 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; Cozi disease; sickle cell retinopathy and / or neovascularizing glaucoma; retinoblastoma.

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