Protein tyrosine kinase inhibitor and medical application thereof

Abstract

The present invention relates to a protein tyrosine kinase inhibitor and its use in the prevention and / or treatment of protein tyrosine kinase mediated hyperproliferative diseases, such as ocular diseases and malignant tumors associated with pathological neovascularization. The protein tyrosine kinase inhibitor not only can effectively antagonize the activity of VEGFR receptor tyrosine kinase, but also improves the pharmacokinetic property of the VEGFR receptor tyrosine kinase, and has high selectivity for inhibiting the activity of off-target EGFR tyrosine kinase so as to reduce or avoid adverse effects, especially side effects on eyes.

Description

Protein tyrosine kinase inhibitor and its medical use Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a protein tyrosine kinase inhibitor and its medical use, in particular its use in the prevention and / or treatment of protein tyrosine kinase-mediated hyperproliferative diseases. Background Art

[0002] Receptor tyrosine kinases play a crucial role in developmental biology, tissue homeostasis, and cancer biology. Receptor tyrosine kinases consist of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular catalytic domain. Dimerization of two receptor tyrosine kinases upon ligand binding leads to autophosphorylation of tyrosine residues within the intracellular catalytic domain, which results in an active conformation and subsequent activation of intracellular signaling cascades. Due to their profound cellular effects, tyrosine kinases are highly regulated. When these kinases become constitutively activated, independent of ligand, through mutation or overexpression, many diseases, such as cancer or ophthalmological disorders like diabetic retinopathy, can develop through unregulated cell proliferation and other mechanisms. For this reason, tyrosine kinase inhibitors offer therapeutic potential for several diseases by interfering with these unregulated processes. The development of RTKi inhibitors (RTKi) targeting pro-angiogenic receptor tyrosine kinases, primarily members of the vascular endothelial growth factor receptor (VEGFR) family, has significantly improved the prognosis of several cancer types, such as renal cell carcinoma, hepatocellular carcinoma, and colorectal cancer, and has become an effective therapeutic approach for treating tumor-associated 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. In particular, DR preferentially manifests neovascularization at the retinal level, while wet AMD is characterized by the formation of new vessels from the choroidal microvascular bed and invasion of the subretinal space. Both DR and AMD are characterized by endothelial cell (EC) proliferation and migration, increased vascular permeability, and inflammation. Vascular endothelial growth factor-A (VEGF-A) and its corresponding receptor (VEGFR) play a key role in these processes. Many proliferative disorders, such as ophthalmic diseases, tumors, and cancers, involve the overexpression or upregulation of receptor tyrosine kinase (RTK) activity. Receptor tyrosine kinases are kinase enzymes that modify proteins by chemically adding phosphate groups (phosphorylation). Phosphorylation typically leads to functional changes in the target protein by altering enzyme activity, cellular localization, or binding to other proteins. Kinases are known to regulate most cellular pathways, particularly those involved in signal transduction. To date, one approach to inhibiting the VEGF pathway has been to inhibit receptor tyrosine kinase (RTK) activity. In the treatment of ocular diseases such as 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, thereby 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) also typically inhibit EGFR activity. This cross-reaction can lead to adverse side effects by inhibiting the biological functions associated with one or more of these off-target receptors. This problem has greatly impacted the application of VEGFR receptor tyrosine kinase inhibitors in the treatment of ophthalmic diseases. To date, the US FDA has not approved small molecule tyrosine kinase inhibitors for the treatment of diabetic retinopathy and neovascular age-related macular degeneration.

[0004] Summary of the Invention

[0005] The present invention provides a compound for the treatment of proliferative diseases or symptoms mediated by protein tyrosine kinases, such as eye diseases and malignant tumors accompanied by pathological neovascularization, which inhibits VEGFR receptor tyrosine kinase activity while having selectivity for EGFR receptor tyrosine kinase inhibition to reduce side effects, especially adverse side effects on the eyes.

[0006] To overcome the deficiencies of the prior art, the present invention provides a protein tyrosine kinase inhibitor and its medical use.

[0007] In a first aspect of the present invention, a compound is provided, which has the following structure:

[0008] in,

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

[0010] B ring is 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 combined with C6-C 10 Aromatic ring, C5-C8 aliphatic ring, 5-10 membered heterocyclic ring fusion;

[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 the group consisting of 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-, and -Cy-; -Cy- is selected from the group consisting of a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, and a substituted or unsubstituted heterocyclylene group;

[0014] L2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted by a group 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; wherein a and b are independently selected from integers of 0-10, R L201 and R L202 Independently selected from: H, C1-C 10 Alkyl, 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 、-NRL204 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, heterocyclyl, heterocyclylalkyl, wherein R L203 and R L204 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] L3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted by a group 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; wherein c and d are independently selected from integers of 0-10, R L301 and R L302 Independently selected from: 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 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, heterocyclyl, heterocyclylalkyl, wherein R L303 and RL304 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 R3 to R5 is independently selected from: 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 is optionally substituted with a group selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0017] R1 is one or more independent substituents on the B ring, each R1 is independently selected from: 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 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-C10 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), -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 the C1-C 10 Alkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group is optionally substituted by a group selected from the group consisting of 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 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted by a group selected from the group consisting of 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 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

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

[0020] R0 is selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -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] Among them, the E ring is 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 combined with C6-C 10 Aromatic ring, C5-C8 aliphatic ring, 4-10 membered heterocyclic ring fusion;

[0022] R2 is selected from: 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 , 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), -SO2(CH2) j (C3-C 10 Cycloalkyl), -S(CH2) j (C3-C 10 Cycloalkyl), -O(CH2) j (C3-C 10 Cycloalkyl), wherein j is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C6-C 10Aryl, 4-10 membered heterocyclic group is optionally substituted by a group selected from the group consisting of 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, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

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

[0024] 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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 Silane, wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted by a group selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0025] 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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 Silane, wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted by a group selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group;

[0026] R' and R" 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, and substituted or unsubstituted heterocyclylalkyl.

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

[0028] In some embodiments of the present invention, Y is -O(CO-C 10 -OH, C1-C3 alkoxy.

[0029] Specifically, ring A is a five-membered or six-membered aromatic ring or heteroaromatic ring. For example, ring A is Wherein, Y1, Y2, Y3 are independently selected from: O, S, N, C (R A ), R A is selected from: H, halogen, substituted or unsubstituted alkyl, hydroxy, alkoxy, amino, alkylamino, cyano, nitro; p is 0 or 1; In some embodiments of the present invention, ring A is in particular

[0030] In one embodiment of the present invention, The section has the following structure:

[0031] Specifically, R A is selected from the group consisting of: H, halogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, amino, C1-C3 alkylamino, cyano, and nitro; in some embodiments of the present invention, R A For H.

[0032] In some embodiments of the present invention, The section has the following structure: in particular

[0033] Specifically, the B ring is a benzene ring or a 5-6 membered monocyclic heterocycle. Optionally, the benzene ring or the 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 invention, Ring B is a benzene ring, a benzoaliphatic ring, or a heterocycle (including a monocyclic heterocycle (particularly a 5-6 membered monocyclic heterocycle), a bicyclic heterocycle (particularly a 9-11 membered bicyclic fused heterocycle)). In some embodiments of the present invention, the 5-6 membered monocyclic heterocycle has the following structure: In some embodiments of the present invention, the benzoaliphatic ring has the following structure: In some embodiments of the present invention, the bicyclic heterocycle has the following structure:

[0035] Specifically, A section can have the following structure:

[0036] In some embodiments of the present invention, ring B is a benzene ring, for example, Part of

[0037] In other embodiments of the present invention, Ring B is a monocyclic heterocycle, particularly a 5-6 membered monocyclic heterocycle, for example Some can be

[0038] In some embodiments of the present invention, The section has the following structure: Among them, R 1b 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl); more specifically, R 1bSelected from: 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 heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5;

[0039] R 1c Selected from: 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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl);

[0040] R 1a 、R 1d 、R 1e Selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), halogen (such as F, Cl, Br, I), 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 R102 、-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);

[0041] Each R 101 and R 102 With the above definition.

[0042] Furthermore, R 1b Can be selected from: -CF3, -CHF2, -CH2F, Cyano, nitro, azido, -OH,

[0043] In some preferred embodiments of the present invention, R 1b -C(O)NR 101 R 102 , where R 101 and R 102 Independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0044] Furthermore, R 1a 、R 1e They can be independently selected from: H, halogen (such as F, Cl), C1-C3 alkyl (such as methyl).

[0045] Preferably, R 1c Can be selected from: H, F.

[0046] Furthermore, R 1d It can be selected from: H, halogen (such as F, Cl), C1-C3 alkyl (such as methyl).

[0047] In some preferred embodiments of the present invention, The section has the following structure:

[0048] In other embodiments of the present invention, Ring B is a bicyclic heterocycle, particularly a 9-11 membered bicyclic fused heterocycle, for example Wherein, the G ring is a 5-6 membered heterocyclic ring, for example Some can be

[0049] In other embodiments of the present invention, Ring B is a fused bicyclic ring, particularly a 9-11 membered fused bicyclic ring, for example Wherein, the F ring is a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring, for example Some can be

[0050] Specifically, each R 101 to R 104 Can be independently selected from: 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 hydroxy-substituted alkyl (e.g., ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 amino substituted 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 heterocyclic group (e.g. C1-C 10 Silyl-substituted alkyl groups (e.g. ), C1-C 10 Silane groups (such as ).

[0051] More specifically, each R 101 to R 104 Independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0052] Specifically, each R1 can be independently selected from: C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), halogen (e.g., F, Cl, Br, I), C1-C6 haloalkyl (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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; specifically, the 4-10 membered heterocycle is a 4-6 membered heterocycle, for example Specifically, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group, for example

[0053] In some embodiments of the present invention, R 102 For H.

[0054] More specifically, each R1 can be independently selected from: C1-C6 alkyl, halogen, 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 heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5, R 101It can be selected from: C1-C6 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl), C1-C6 haloalkyl (e.g. -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3), C3-C6 cycloalkyl (e.g. ), C4-C 10 Cycloalkylalkyl ( ).

[0055] In some embodiments of the present invention, each R1 is independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH,

[0056] In one embodiment of the present invention, R0 is

[0057] In some embodiments of the present invention, the E ring is a 4-10 membered (e.g., 4, 5, 6, 7, 8, 9, 10 membered) heterocycle, in particular a 4-8 membered saturated heterocycle (including monocyclic, polycyclic, such as fused, spiro or bridged polycyclic), for example, In particular, a 5-7 membered nitrogen-containing heterocycle, for example,

[0058] In some embodiments of the present invention, Part of

[0059] Specifically, each R 201 to R 204 Can be independently selected from: 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 hydroxy-substituted alkyl (e.g., ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 amino-substituted 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 heterocyclic group (e.g. ),

[0060] More specifically, each R 201 to R 204 Can be independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0061] Specifically, R2 can be selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 heterocyclic group), -(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 10 Cycloalkyl is a C3-C6 cycloalkyl group, for example

[0062] More specifically, R2 can be selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, halogen, halogen, cyano, nitro, azido, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0063] In some embodiments of the present invention, R2 is selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, hydroxy, methoxy, ethoxy,

[0064] In some embodiments of the present invention, R0 is selected from:

[0065] In one embodiment of the present invention, R0 is -NR 001 R 002 , where R 001 and R 002 independently selected from the group consisting of: 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.

[0066] Specifically, R 001 and R 002 Independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0067] In some embodiments of the present invention, R0 is selected from:

[0068] In other embodiments of the present invention, R0 is selected from: H, cyano, -O(CO-C 10 Alkyl), -O(C1-C 10 Silane), -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-C10 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 by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl; for example, R0 is selected from the group consisting of: H, cyano, -OH, -COOH,

[0069] Specifically, R3 to R5 are independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy substituted alkyl, C1-C6 alkylamino substituted alkyl, C3-C6 cycloalkyl, C4-C6 alkyl, 10 Cycloalkylalkyl; more specifically, R3 to R5 are independently selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

[0070] In some embodiments of the present invention, R3 is H.

[0071] In some embodiments of the present invention, R4 is H.

[0072] In some embodiments of the present invention, R5 is H.

[0073] Specifically, -Cy- can be selected from:

[0074] 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 group; more specifically, each R 10 Independently selected from: H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl.

[0075] In one embodiment of the present invention, L1 is -C(O)NR3-, and R3 has the above definition of the present invention.

[0076] In some embodiments of the present invention, L1 is -C(O)NH-.

[0077] In another embodiment of the present invention, L1 is -Cy-, and -Cy- has the above definition of the present invention.

[0078] In some embodiments of the present invention, -Cy- is selected from:

[0079] In another embodiment of the present invention, L1 is a single bond.

[0080] In another embodiment of the present invention, L1 is -C(O)-.

[0081] Specifically, for the definition of L2, a and b are independently selected from: 0, 1, 2, 3, 4, 5.

[0082] Specifically, for the definition of L2, R L203 and R L204 Can 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.

[0083] Specifically, L2 is a single bond or C2-C 10 Alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the group consisting of: -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 by a group consisting of: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; more specifically, L2 is C2-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the group consisting of: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-.

[0084] In some embodiments of the present invention, L2 is selected from: a single bond,

[0085] Specifically, for the definition of L3, c and d are independently selected from: 0, 1, 2, 3, 4, 5.

[0086] Specifically, for the definition of L3, R L303 and R L304Can 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.

[0087] Specifically, L3 is C1-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the following: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, wherein one or more H atoms in the alkylene are optionally and independently substituted by a group selected from the following: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; in some embodiments of the present invention, L3 is methylene (-CH2-).

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

[0089] In one embodiment of the present invention, the compound has the following structure:

[0090] Among them, R 11 C1-C 10 alkyl.

[0091] Specifically, R 11 It is C1-C6 alkyl, especially C1-C3 alkyl, such as methyl and ethyl.

[0092] In some embodiments of the present invention, the compound has the following structure:

[0093] In a second aspect of the present invention, pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds of the compound of the first aspect are provided.

[0094] In some embodiments of the present invention, the stereoisomer has the following structure:

[0095] In the third aspect of the present invention, an intermediate compound is provided, which can be used to prepare the first aspect of the present invention wherein Y is -N(C0-C 10 Alkyl)(C0-C 10 alkyl) compound (for example, the compound represented by formula II), the intermediate compound has the following structure:

[0096] Among them, R 12 is an alkyl group;

[0097] Ring A, Ring B, X1, L1, L2, L3, R1, R0, and m have the definitions described in the first aspect of the present invention.

[0098] Specifically, R 12 It is C1-C6 alkyl, especially C1-C3 alkyl, such as methyl and ethyl.

[0099] In one embodiment of the present invention, the intermediate compound has the following structure:

[0100] Specifically, the intermediate compound represented by formula V can be subjected to a one-step aminolysis (eg, by reacting with an alcoholic ammonia solution or aqueous ammonia) to obtain the compound represented by formula II.

[0101] In the fourth aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, and one or more pharmaceutically acceptable excipients.

[0102] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of: disintegrants, binders, lubricants, suspending agents, stabilizers, fillers, absorption enhancers, surfactants, flavoring agents, antioxidants, preservatives, and the like.

[0103] Specifically, in the pharmaceutical composition, the compound described in the first aspect, or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, can be used alone or in combination with other types of active ingredients.

[0104] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.). In some embodiments of the present invention, the pharmaceutical composition is administered by intraocular administration (e.g., eye drops, eye ointment, subconjunctival injection, intraocular injection).

[0105] Specifically, the pharmaceutical composition can be in any suitable dosage form, such as a gastrointestinal dosage form, for example, including but not limited to tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, suspensions, etc.; parenteral dosage forms, for example, injectable dosage forms: such as injections (for example, for subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), respiratory tract dosage forms: such as sprays, aerosols, powder mists, etc., skin dosage forms, such as external solutions, lotions, ointments, plasters, pastes, patches, etc., mucosal dosage forms: such as eye drops, eye ointments, nasal drops, gargles, sublingual tablets, etc., cavity dosage forms: such as suppositories, aerosols, effervescent tablets, drops, pills, etc., for rectum, vagina, urethra, nasal cavity, ear canal, etc.

[0106] In some embodiments of the present invention, the pharmaceutical composition is an ophthalmic preparation, such as eye drops or eye ointments.

[0107] Specifically, the various dosage forms of the above-mentioned pharmaceutical composition can be prepared according to conventional production methods in the pharmaceutical field, for example, by mixing the active ingredient with one or more pharmaceutically acceptable excipients and then preparing the mixture into the desired dosage form.

[0108] Specifically, in the above-mentioned pharmaceutical composition, the weight percentage of the compound described in the first aspect, or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound can be 0.1-99.5%, for example, 0.5%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, and especially 1-30%.

[0109] In a fifth aspect of the present invention, there is provided use of the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate or deuterated compound thereof, in the preparation of a drug for inhibiting protein tyrosine kinase activity.

[0110] Specifically, the protein tyrosine kinase may be VEGFR, EGFR, or TIE2; in particular, the activity of VEGFR is inhibited.

[0111] Specifically, the drug is a drug that selectively inhibits VEGFR.

[0112] In the sixth aspect of the present invention, there is provided the use of the compound described in the first aspect, or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, in the preparation of drugs for preventing and / or treating proliferative diseases mediated by protein tyrosine kinase.

[0113] In one embodiment of the present invention, 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, renal cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, unrelated myeloid metaplasia, mesothelioma, myelodysplastic syndrome, and hematological malignancies.

[0114] Specifically, hematological malignancies include leukemia, lymphoma, and multiple myeloma (MM).

[0115] Specifically, the leukemia may be chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or acute monocytic leukemia.

[0116] Specifically, the lymphoma may be Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, Tumors and primary central nervous system (CNS) lymphomas and T-cell NHL, such as precursor T lymphoblastic lymphoma / leukemia, peripheral T cell lymphoma (PTCL), angioimmunoblastic T cell lymphoma, extranodal natural killer T cell lymphoma, enteropathy-type T cell lymphoma, subcutaneous panniculitis-like T cell lymphoma and anaplastic large cell lymphoma, NK / T cell lymphoma, particularly diffuse large B cell lymphoma (DLBCL). Specifically, in the application, the treatment of the tumor includes killing the tumor, preventing the metastasis and spread of the tumor and the growth of micrometastasis.

[0117] In one embodiment of the present invention, the disease is an eye disease, including, but not limited to, diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema); age-related macular degeneration (AMD) (including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy); pathological choroidal neovascularization (CNV) arising from any pathological mechanism (i.e., high myopia, trauma, sickle cell (anemia) disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophies); pathological visual atrophy arising from any pathological mechanism. Retinal neovascularization (i.e., sickle cell retinopathy, Eales disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteritis, birdshot retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis); uveitis; retinal vein occlusion (central or branch); ocular trauma; surgical edema; surgical neovascularization; cystoid macular edema; ocular ischemia; retinopathy of prematurity; Coat's disease; sickle cell retinopathy and / or neovascular glaucoma.

[0118] In some embodiments of the present invention, the disease is diabetic retinopathy, including simple (background) diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema.

[0119] In other embodiments of the present invention, the disease is age-related macular degeneration (AMD), including neovascular (wet / exudative) AMD, dry AMD, and geographic atrophy.

[0120] In the seventh aspect of the present invention, a method for inhibiting protein tyrosine kinase activity is provided, which comprises the step of administering to a subject in need thereof the compound of the first aspect, or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds or the pharmaceutical composition of the fourth aspect of the present invention.

[0121] Specifically, 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, inhibiting VEGFR (especially VEGFR2) activity.

[0122] Specifically, the method is a method for selectively inhibiting VEGFR.

[0123] Specifically, the above-mentioned subject can be a mammal, especially a human.

[0124] Specifically, the method is performed in vivo, or in vitro.

[0125] In the eighth aspect of the present invention, a method for preventing and / or treating a proliferative disease mediated by protein tyrosine kinase is provided, comprising the step of administering to a subject in need thereof the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuterated compound thereof, or the pharmaceutical composition of the fourth aspect of the present invention.

[0126] Specifically, the disease is as described in the sixth aspect of the present invention.

[0127] Specifically, the above-mentioned subject can be a mammal, especially a human.

[0128] In the ninth aspect of the present invention, a method for inhibiting ocular neovascularization and retinal vascular leakage is provided, which comprises the step of administering to a subject in need thereof the compound of the first aspect, or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates and deuterated compounds, or the pharmaceutical composition of the fourth aspect of the present invention.

[0129] Specifically, the administration can be carried out by any suitable administration route, in particular intraocular administration, such as eye drop administration, eye ointment administration, subconjunctival injection administration, intraocular injection administration, in particular eye drop administration.

[0130] Specifically, the above-mentioned subject can be a mammal, especially a human.

[0131] The present invention provides a series of compounds that have the ability to inhibit anti-angiogenic tyrosine kinases. In addition to effectively antagonizing the tyrosine kinase activities of VEGFR1, VEGFR2, and VEGFR3, they are highly selective in inhibiting the tyrosine kinase activity of EGFR, and can effectively reduce or even completely avoid side effects, especially side effects on the eyes (such as epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosion and / or corneal edema, keratitis). They have excellent application and research value. DETAILED DESCRIPTION

[0132] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0133] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is completely saturated or contains one or more unsaturated units (also referred to herein as "aliphatic ring", "cycloalkyl"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl 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.

[0134] The term "carbocycle" is composed entirely of carbon atoms and can be divided into aliphatic rings and aromatic rings.

[0135] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected 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, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted by a cycloalkyl group, it is correspondingly a "cycloalkylalkyl" group, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, it is correspondingly an "aralkyl" group, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted by a heterocyclic group, it is correspondingly a "heterocyclylalkyl" group. In the present invention, a C0 alkyl group refers to H, i.e., C 0-10 Alkyl groups include H and C 1-10 alkyl.

[0136] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene includes single bonds and C 1-10 Alkylene.

[0137] The term "cycloalkyl" refers to alicyclic hydrocarbons, such as those containing 1 to 4 single rings and / or condensed rings, containing 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0138] The term "alkoxy" refers to a substituent formed by replacing the hydrogen of a hydroxy group with an alkyl group, such as an alkoxy group containing 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, and the like.

[0139] The term "alkylamino" refers to a substituent formed when one or both hydrogen atoms in an amino group (-NH2) are replaced by an alkyl group, such as an alkylamino group containing 1 to 10 carbon atoms, for example

[0140] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0141] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms in an alkyl group with a halogen atom (such as fluorine, chlorine, bromine or iodine), for example, -CHF2, -CH2F, -CF3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0142] The term "aryl" refers to a monocyclic or polycyclic free radical, including a polycyclic free radical containing a monocyclic aromatic group and / or a condensed aromatic group, such as a radical containing 1-3 monocyclic or condensed rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. 12 The aryl group refers to an aryl group containing 6 to 12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0143] The term "heterocyclyl" refers to a 3- to 18-membered ring radical containing 2- to 17 carbon atoms and 1- to 10 heteroatoms selected from nitrogen, oxygen, or sulfur atoms. A heterocyclyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. Polycyclic ring systems may include fused (two rings share two ring atoms), spiro-connected (two rings share one ring atom), or bridged (two rings share three or more ring atoms) ring systems (excluding linked rings). A heterocyclyl may be partially saturated (heteroaryl) or fully saturated (heterocycloalkyl). Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms and include, for example, coumarin, including 8-coumarin, quinolyl, including 8-quinolyl, isoquinolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl. Suitable heterocycloalkyl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms, and include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepine, oxazepine, diazepine, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothiolanyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinolizinyl.

[0144] The term "optionally substituted" group may 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(O) 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 Heterocyclic group, C 3-8 Heterocyclylalkyl; t is 0, 1 or 2; each R' and R" are independently selected from: H, halogen, -CN, -NO2, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl; or, R' and R" attached to the same nitrogen atom together with the nitrogen atom form a heterocycle.

[0145] The term "pharmaceutically acceptable salts" includes acid addition salts and base addition salts.

[0146] The term "acid addition salt" includes, but is not limited to, salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids, for example, acetate, salicylate, decanoate, stearate, oleate, hexanoate, malate, glycolate, ethanesulfonate, isethionate, and the like. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate, aspartate, glutamate etc.Acid addition salts can be prepared by making the free alkali form contact the mode of forming salt with sufficient required acid in a conventional manner.Can regenerate free alkali form by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0147] The term "base addition salt" refers to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0148] The term "stereoisomer" includes the presence of enantiomers, diastereomers and geometric isomers. Some compounds of the present invention have cyclic hydrocarbon groups that may be substituted on more than one carbon atom, in which case all geometric forms, including cis and trans forms, and mixtures thereof, are within the scope of the present invention.

[0149] The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules. This physical association includes varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates include solution phases and isolatable solvates. Representative solvates include ethanolates, methanolates, and the like.

[0150] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms, are replaced by deuterium atoms (D).

[0151] It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will exist in the synthesized compounds. Therefore, the compounds of the present invention will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of these naturally abundant stable hydrogen and carbon isotopes are low and insignificant compared to the degree of stable isotopic substitution in the compounds of the present invention. See, for example, Wada, E. et al., Seikagaku, 1994, 66:15; Gannes, L.Z. et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0152] In the compounds of the present invention, any atom not designated as deuterium is present at its natural isotopic abundance. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Similarly, unless otherwise indicated, when a position is specifically designated as "D" or "deuterium," the position is understood to have deuterium at an abundance of at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).

[0153] As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope.

[0154] In other embodiments, the compounds of the invention have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated 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).

[0155] The term "isotopologue" refers to a substance wherein the chemical structure differs from a specific compound of the present invention only in its isotopic composition.

[0156] The term "prodrug" refers to a form of a compound of Formula I that is suitable for administration to a patient without undue toxicity, irritation, allergic reactions, etc., and is effective for its intended use, including acetal, ester, and zwitterion forms. The prodrug is transformed in vivo, for example, by hydrolysis in the blood, to yield the parent compound.

[0157] The terms "patient" or "subject" and the like are used interchangeably herein to refer to any animal or cell thereof to be treated according to the methods described herein, whether in vitro or in situ. Specifically, the aforementioned animals include mammals, e.g., rats, mice, guinea pigs, rabbits, dogs, monkeys, humans, and particularly humans.

[0158] The term "treating" refers to preventing, curing, reversing, attenuating, alleviating, minimizing, inhibiting, suppressing and / or halting one or more clinical symptoms of a disease after onset of the disease.

[0159] The term "prevent" or "prevent" refers to treating a disease before it occurs to avoid, minimize, or make the onset or development of the disease more difficult.

[0160] The term "tumor" refers to an abnormal mass of tissue, wherein the growth of the mass exceeds the growth of normal tissue and is not coordinated with the growth of normal tissue. Tumors can be "benign" or "malignant", depending on the following characteristics: the degree of cell differentiation (including morphology and function), growth rate, local invasion and metastasis. "Benign tumors" are usually well differentiated, characterized in that they grow slower than malignant tumors and remain confined 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 may later lead to malignant tumors, which may be due to additional genetic changes in a subpopulation of the tumor's neoplastic cells, and these tumors are called "precancerous tumors". "Malignant tumors" are usually poorly differentiated (anaplastic) and have a characteristic rapid growth, accompanied by progressive infiltration, invasion and destruction of surrounding tissues. In addition, malignant tumors usually have the ability to metastasize to distant sites.

[0161] The term "cancer" refers to a malignant tumor (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990).

[0162] The term "protein tyrosine kinase inhibitor" refers to a molecule that reduces, inhibits, or otherwise decreases one or more biological activities of a protein tyrosine kinase. Inhibition using a protein tyrosine kinase inhibitor does not necessarily indicate complete elimination of protein tyrosine kinase activity. Protein tyrosine kinase activity may be reduced by a significant amount, e.g., protein tyrosine kinase activity is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, compared to a control.

[0163] Unless otherwise stated, numerical ranges expressed in the format "from x to y" or "xy" should be understood to include x and y. When, for a specific feature, multiple preferred ranges are described in the format "from x to y" or "xy", it should be understood that all ranges combining the different endpoints are also contemplated.

[0164] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0165] Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are known as the most powerful vascular permeability agents and endothelial cell-specific, playing a key role in endothelial cell proliferation, migration, and angiogenesis. Angiogenesis is a crucial mechanism in many physiological and pathological processes, participating in the proliferation, migration, and survival of endothelial cells, leading to further capillary formation and ultimately promoting blood vessel formation. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) play an important role in angiogenesis associated with pathologies such as tumor development and ocular neovascularization. For example, VEGF expression levels are significantly positively correlated with the degree of vascularization in tumor tissue. VEGF acts on VEGFR receptors, activating the phosphorylation of VEGFR receptor tyrosine kinase and leading to the transduction of abnormal cell signals, thereby promoting endothelial cell proliferation and neovascularization. It is a major player in many different cancers and ocular diseases accompanied by pathological neovascularization. However, despite efforts to design VEGFR receptor-specific molecules, some cross-reactions with other "off-target" receptors are inevitable, such as inhibition of TIE2 receptors (i.e., TEK tyrosine kinases) or EGFR receptor activity. Clinically, it has been observed that receptor tyrosine kinase inhibitors inhibit EGFR while inhibiting VEGFR, affecting EGFR-mediated corneal epithelial wound healing, thereby causing adverse side effects on the eyes. In addition, TIE2 plays a vital role in maintaining vascular integrity. Its inhibition can lead to weakened endothelial cell connections, promote fluid leakage and eye edema, impair retinal blood flow and oxygen delivery, and may lead to vision loss. The compounds of the present invention have significantly improved selectivity for inhibiting TIE2 and EGFR. Not only does it improve the antagonism of the tyrosine kinase activity of all VEGFR receptors (VEGFR1, VEGFR2, VEGFR3), but it also significantly improves the selectivity for inhibiting TIE2 and EGFR receptor activity (as shown in the test examples).

[0166] VEGFR2 is the primary receptor for VEGF-induced endothelial cell signaling. During development and / or after tissue damage, upon binding of the ligand VEGF to the receptor, VEGFR2 undergoes autophosphorylation and becomes activated, inducing angiogenesis and bypassing blocked blood vessels. Clinical treatment targeting the vascular endothelial growth factor (VEGF-A) / VEGFR2 signaling pathway has been shown to be an effective approach for treating ocular neovascularization diseases such as wet AMD. The compounds of the present application have a significant inhibitory effect on VEGF-induced VEGFR2 autophosphorylation (pVEGFR2) in human endothelial cells, thereby blocking signal transduction in abnormal cells and inhibiting neovascularization (as shown in the test examples). The primary function of VEGFR receptor signaling is to promote endothelial cell proliferation and neovascularization. The compounds of the present application have been shown to have the ability to inhibit VEGF-induced human endothelial cell proliferation at nanomolar concentrations (as shown in the test examples). In summary, the compounds of the present application are novel tyrosine kinase inhibitors. In addition to being used to treat neovascular age-related macular degeneration and diabetic retinopathy, this new type of tyrosine kinase inhibitor can also be used in tumor indications by blocking the formation of new tumor blood vessels, blocking the blood and nutrient supply required for tumor growth, and leading to tumor cell death.

[0167] Although the U.S. Food and Drug Administration (FDA) has approved aflibercept (VEGF Trap-Eye) for the treatment of neovascular age-related macular degeneration and diabetic retinopathy. However, aflibercept is a 115kDa fully human recombinant protein that needs to be administered by intravitreal injection. For clinicians and patients, frequent intravitreal injections are not only inconvenient, but also have rare but serious injection-related risks (retinal detachment, endophthalmitis, intraocular inflammation, cataracts, etc.). Therefore, many patients do not inject on time and the drug efficacy is poor. The compound of the present invention (small molecule VEGFR tyrosine kinase inhibitor) represents another method of directly targeting VEGF to replace VEGF antibody biologics. The good clinical results of VEGF antibody biologics have verified the role of the VEGF pathway in neovascular age-related macular degeneration and diabetic retinopathy. Compared with monoclonal antibodies, small molecule targeted VEGFR tyrosine kinase inhibitors have many advantages. By virtue of their ability to inhibit all members of the VEGFR family, VEGF signaling can be effectively inhibited. It can be made into eye drops to avoid intravitreal injection, can cross the cell membrane and directly interact with the cytoplasmic domain of receptor tyrosine kinase (RTK). And small molecule eye drops are less economical 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 its "target" toxicity. Inhibiting VEGFR in healthy vasculature has the potential to cause serious adverse events such as hypertension, bleeding and thrombosis. Despite many clinical successes in tumor indications, the safety of oral VEGFR-2 inhibitors may be the main reason why their clinical use and / or development are limited in clinical use in patients with age-related macular degeneration and diabetic retinopathy. Therefore, compared with oral VEGFR-2 inhibitors, topical eye drops can provide an effective therapy that limits systemic exposure and avoids target toxicity issues.

[0168] While topical ocular drug delivery has proven to be a successful strategy for treating diseases related to the anterior aspect of the eye, such as glaucoma, there are currently no FDA-approved topical therapies for ocular diseases related to the posterior ocular tissues, such as the retina and choroid, such as neovascular AMD and diabetic retinopathy. This is largely due to the anatomical and physiological barriers that have evolved in the human eye to protect it from exogenous substances. The tear film is one of the first barriers to overcome. Compounds in the anterior aspect of the eye can be rapidly washed away by the tear film, leading to nasolacrimal drainage. Therefore, compounds may need to be rapidly absorbed after topical instillation. However, absorption / penetration into ocular tissues can also be challenging. One absorption pathway involves penetration through the cornea. The cornea is composed of an epithelium with tight junctions and alternating lipophilic and hydrophilic layers. Another absorption pathway involves penetration into the conjunctiva and subsequent diffusion into the sclera. The sclera is a relatively more permeable ocular tissue. However, drugs that enter the conjunctiva tend to be "lost" to the systemic circulation due to the highly vascularized nature of this tissue. Compounds exposed in the sclera have the potential to diffuse into the choroid. The choroid is a primary target tissue for neovascular AMD. Diffusion from the choroid to the retina (a target tissue for neovascular AMD) is further attenuated across the blood-retinal barrier (BRB). The BRB functions similarly to the blood-brain barrier and can be a formidable barrier to compound diffusion. Due to these anatomical and physiological barriers, it is estimated that less than 5% of a topically administered dose reaches the posterior ocular tissues. Despite these challenges associated with topical delivery, the present invention focuses on developing structure-activity relationships (SARs) related to ocular and blood exposure. Effective delivery to the posterior ocular tissues is achieved through ocular and blood exposure-containing eye drop formulations (as demonstrated in the test examples). Rapid degradation of the compounds in plasma suggests, on the one hand, that exposure of the compounds of the present invention to the posterior ocular tissues is via distribution at the instillation site and not from systemic blood. On the other hand, the low plasma, or systemic, exposure of these compounds helps avoid systemic target toxicity concerns. Furthermore, significant exposure was observed in the sclera, indicating that these compounds are effectively delivered to the posterior ocular tissues (choroid and retina) primarily through the sclera. Some exposure to the posterior ocular tissues (choroid and retina) was also observed 8 hours after administration. The present invention provides novel compounds that achieve sufficient drug concentration in the posterior segment of the eye (such as the choroid and retina) to bind to relevant receptors targeting the eye, increase bioavailability in the posterior segment of the eye, and improve the problems encountered in the ocular delivery of existing local therapeutic agents.

[0169] One of the goals of medicinal chemistry is to improve the bioavailability and stability of compounds, thereby enhancing their efficacy. Bioavailability refers to the rate and extent to which a therapeutic agent is absorbed from a pharmaceutical form and becomes available at the site of action. Existing inhibitors of tyrosine kinases (such as VEGFR1, VEGFR2, and VEGFR3) suffer from low solubility and / or limited kinase inhibitory activity, significantly impacting the bioavailability of these compounds and consequently reducing their efficacy. The present invention provides compounds that may exhibit enhanced solubility and / or significant kinase inhibitory activity (as demonstrated in the test examples). Furthermore, test results provide the percentage of free drug in the compounds of the present invention, meaning that the drug is not bound to melanin and is able to interact with receptors in ocular tissues (as demonstrated in the test examples). Melanocytes in the eye are located in the retinal pigment epithelium at the back of the eye, the choroid, the ciliary body at the front of the eye, and the iris. Compound binding to melanin may affect ocular pharmacokinetics following topical administration. The present invention provides an eye drop formulation containing the compounds for the treatment of age-related macular degeneration and diabetic retinopathy. These are diseases of the posterior segment of the eye, and eye drop formulations containing compounds are targeted for efficient delivery to the posterior ocular tissues. In these cases, the drug may bind to melanin-producing tissues in the posterior eye (retinal pigment epithelium, choroid) or anterior eye (ciliary body, iris). Many clinical drugs bind to melanin, thus affecting their ocular pharmacokinetics. The rate of compound binding to melanin is an important factor in ocular pharmacokinetics and pharmacodynamics and must be considered in drug discovery and development.

[0170] Since many eye drops have limited permeability through the corneal and conjunctival barriers, a major limitation of eye drops may be the need for high concentrations of compounds in the ocular formulation in order to achieve effective therapeutic drug levels in the posterior ocular tissues. Depending on the compound (the molecule itself or its high concentration), the ocular formulation may have side effects on the anterior ocular tissues (including the conjunctiva, cornea and / or lens), leading to various ocular surface damage, such as corneal epithelial defects and erosions. In particular, it has been observed clinically that treatment with EGFR antibody drugs may cause ocular side effects, such as epithelial degeneration and defects, ulcers, corneal epithelial thinning, erosion and / or corneal edema, and keratitis. EGFR is a major factor in wound healing in human corneal epithelial cells. Therefore, it is very necessary to select compounds for topical ocular formulations that avoid inhibiting EGFR activity. In addition to effectively antagonizing the tyrosine kinase activity of VEGFR1, VEGFR2, and VEGFR3, the compounds of the present invention are highly selective for inhibiting EGFR tyrosine kinase activity (as shown in the test examples). The inventors used male Dutch Blackbelt rabbits to assess the maximum tolerated dose (MTD) of the compounds for ocular administration, helping to select the dose with the least toxicity and highest potential efficacy for in vivo animal efficacy studies. Results showed that on the third day of ocular administration, the maximum tolerated dose (MTD) was 100 μg / eye for PAN90806 and 250 μg / eye or higher for T093. The inventors further administered ocular drops to the rabbits for six consecutive days to assess the ocular toxicity risk of T093 and PAN90806. Results showed that no abnormalities were observed in the eyes of any rabbit in the T093 (250 μg / eye) group, while the MTD for the positive compound PAN90806 was reduced to 50 μg / eye. T078 and T116 were administered ocularly at a dose of 1000 μg / eye for three consecutive days, and the toxicity risk assessment showed no abnormalities were observed in any rabbit. Therefore, the maximum tolerated dose (MTD) of T078 and T116 on the fourth day of eye drop administration was 1000 μg / eye or higher.

[0171] The present invention provides a compound of formula I, particularly compounds of formula II and III, and their medical uses.

[0172] In one embodiment (1) of the present invention, in Formula I, especially Formula II and III, L1 is -C(O)NR3- or a single bond, Part of Wherein, R1 contains at least one of the following groups: 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5, E ring and R2 have the corresponding definitions as defined above in the present invention.

[0173] Specifically, each R 101 and R 102 Can be 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-C 10 Cycloalkyl, C4-C 10 cycloalkylalkyl, substituted or unsubstituted 4-10 membered heterocyclic group, C1-C 10 Silane-substituted alkyl, C1-C 10 Silane group.

[0174] More specifically, each R 101 and R 102 Can be independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0175] In some embodiments of the present invention, each R 101 and R 102 Independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0176] In some embodiments of the present invention, R 102 For H.

[0177] In some embodiments of the present invention, R 101 Selected from: methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F,

[0178] More specifically, R1 comprises at least one of the following groups: 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 heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5.

[0179] More specifically, R1 may also include a group selected from the following: C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl), halogen (e.g., F, Cl, Br, I). In some embodiments of the present 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, azido, -OH, More specifically, R1 may also include a group selected from the following: C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), halogen (such as F, Cl, Br, I).

[0180] In some embodiments of the present invention, The section has the following structure: Among them, R 1b 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 、-SR 101 、-S(O)2R 101、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl); more specifically, R 1b Selected from: 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 heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5;

[0181] R 1c Selected from: 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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl);

[0182] R 1a 、R 1d 、R 1e Selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), halogen (such as F, Cl, Br, I), 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl);

[0183] Each R 101 and R 102 With the above definition.

[0184] Furthermore, R 1b Can be selected from: -CF3, -CHF2, -CH2F, Cyano, nitro, azido, -OH,

[0185] In some embodiments of the present invention, R 1b -C(O)NR 101 R 102 , where R 101 and R 102 Independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl.

[0186] Furthermore, R 1a 、R 1e They can be independently selected from: H, halogen (such as F, Cl), C1-C3 alkyl (such as methyl).

[0187] Furthermore, R 1c Can be selected from: H, F.

[0188] Furthermore, R 1d It can be selected from: H, halogen (such as F, Cl), C1-C3 alkyl (such as methyl).

[0189] In some embodiments of the present invention, The section has the following structure:

[0190] In some embodiments of the present invention, L1 is -C(O)NR3-, R0 is

[0191] In some embodiments of the present invention, R0 is selected from: H, cyano, -O(CO-C 10 Alkyl), -O(C1-C 10 Silane), -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 by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl; more specifically, R0 is selected from: H, cyano, -OH, -COOH,

[0192] In some embodiments of the present invention, L2 is C0-C 10 Alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted by H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; more specifically, L2 is C0-C6 alkylene.

[0193] In some embodiments of the present invention, L1 is a single bond, L2 is a single bond, and R0 is H, that is, the compound has the following structure: in particular Has the definition as above.

[0194] In some embodiments of the present invention, the compound has the following structure:

[0195] In one embodiment (2) of the present invention, in formula I, especially formula II and III, L1 is -C(O)NR3-, and ring B is a monocyclic heterocycle, especially a 5-6 membered monocyclic heterocycle, for example Some can be Wherein, R1 has the above definition of the present invention.

[0196] Specifically, each R1 can be independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, 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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5.

[0197] In some embodiments of the present invention, each R1 can be independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OH, C1-C6 alkoxy.

[0198] More specifically, each R1 can be independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH,

[0199] In some embodiments of the present invention, L1 is -C(O)NR3-, R0 is

[0200] In some embodiments of the present invention, R0 is selected from: H, cyano, -O(CO-C 10 Alkyl), -O(C1-C 10 Silane), -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 by a group selected from the group consisting of: halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl; more specifically, R0 is selected from the group consisting of: H, cyano, -OH, -COOH,

[0201] In some embodiments of the present invention, L2 is C0-C 10 Alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted by H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; more specifically, L2 is C0-C6 alkylene.

[0202] In some embodiments of the present invention, the compound has the following structure:

[0203] In one embodiment (3) of the present invention, in formula I, especially formula II and III, L1 is -C(O)NR3-, and ring B is a bicyclic ring, especially a 9-11 membered fused bicyclic ring, for example Some can be Wherein, R1 has the above definition of the present invention.

[0204] Specifically, each R1 can be independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, 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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5.

[0205] In some embodiments of the present invention, each R1 can be independently selected from: H, C1-C6 alkyl, C1-C6 haloalkyl, halogen, -OH, C1-C6 alkoxy.

[0206] More specifically, each R1 is independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH, In some embodiments of the present invention, each R1 is independently selected from: H, methyl, ethyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH.

[0207] In some embodiments of the present invention, L1 is -C(O)NR3-, R0 is

[0208] In some embodiments of the present invention, R0 is selected from: H, cyano, -O(CO-C 10 Alkyl), -O(C1-C 10 Silane), -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 by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl; more specifically, R0 is selected from: H, cyano, -OH, -COOH,

[0209] In some embodiments of the present invention, L2 is C0-C 10 Alkylene, wherein one or more H atoms in the alkylene are optionally and independently substituted by H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 Cycloalkylalkyl; more specifically, L2 is C1-C6 alkylene.

[0210] In some embodiments of the present invention, the compound has the following structure:

[0211] In one embodiment (4) of the present invention, in Formula I, especially Formula II and III, L1 is -Cy-, and Ring B and R0 have the above definitions of the present invention.

[0212] In some embodiments of the present invention, L1 is -Cy-, R0 is

[0213] In some embodiments of the present invention, L1 is -Cy-, R0 is -NR 001 R 002 .

[0214] In some embodiments of the present invention, -Cy- is selected from:

[0215] 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 by a group selected from the group consisting of: -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 by a group consisting of: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 More specifically, L2 is C2-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the following: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-. Specifically, L2 can be selected from: a single bond,

[0216] Specifically, A section can have the following structure:

[0217] In some embodiments of the present invention, The section has the following structure: More specifically, R1 is selected from the group consisting of: C1-C6 alkyl, halogen, C1-C6 haloalkyl, cyano, nitro, azido, -O(C0-C 10 Alkyl), -S(C0-C 10 alkyl), -C(O)(C0-C 10alkyl), -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 by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, and C3-C6 cycloalkyl; more specifically, R1 is selected from the group consisting of halogen (e.g., F, Cl, Br). In one embodiment of the present invention, Part of

[0218] In some embodiments of the present invention, the compound has the following structure:

[0219] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0220] Synthesis Example:

[0221] Example 1: Synthesis of Compound T002

[0222] The synthetic route is as follows:

[0223] first step

[0224] (1-methyl-1H-indazol-3-yl)methanol

[0225] (1-Methyl-1H-indazol-3-yl)methanol

[0226] 1-Methyl-1H-indazole-3-carboxylic acid I001 (2.0 g, 11.4 mmol) was dissolved in anhydrous THF (20 mL). The temperature was lowered to -78°C under N2 protection, and DIBAL-H (22.8 mL, 1 M in hexane, 22.8 mmol) was added dropwise. The reaction system was slowly warmed to room temperature and stirred for 1 hour. The reaction system was cooled to 0°C and quenched with 1 M aqueous HCl (30 mL). The mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide (1-methyl-1H-indazol-3-yl)methanol I002 (1.2 g, yellow liquid) in a yield of 65%.

[0227] MS-ESI calculated value [M+H] + 163.1, measured 162.9.

[0228] Step 2

[0229] (1-methyl-1H-indazol-3-yl)methyl 4-methylbenzenesulfonate

[0230] Methyl (1-methyl-1H-indazol-3-yl)-4-methylbenzenesulfonate

[0231] (1-Methyl-1H-indazol-3-yl)methanol I002 (1.2 g, 7.4 mmol), triethylamine (1.5 g, 14.8 mmol), and DMAP (90 mg, 0.7 mmol) were dissolved in DCM (30 mL). The temperature was lowered to 0°C under N2(g) protection, and TsCl (1.6 g, 8.2 mmol) was added. The reaction system was stirred at 0°C for 2 hours. The reaction solution was washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified using a chromatography column (PE:EA = 10:1) to obtain (1-methyl-1H-indazol-3-yl) 4-methylbenzenesulfonic acid methyl ester I003 (400 mg, white solid) in a yield of 23%.

[0232] Step 3

[0233] dimethyl 2-(mercapto(methylthio)methylene)malonate

[0234] Dimethyl 2-(mercapto(methylthio)methylene)malonate

[0235] Under N₂ protection, DBU (9.2 g, 60.6 mmol) was dissolved in ACN (30 mL). Dimethyl malonate (1004) (4.0 g, 30.3 mmol) was added dropwise in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes, followed by the dropwise addition of carbon disulfide (2.3 g, 30.3 mmol). The mixture was stirred in an ice-water bath for 1 hour. Dimethyl sulfate (3.8 g, 30.3 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was warmed to 25°C and stirred for 2 hours to obtain crude dimethyl 2-(mercapto(methylthio)methylene)malonate (1005), which was used directly in the next step.

[0236] Step 4

[0237] methyl 3-hydroxy-5-(methylthio)isothiazole-4-carboxylate

[0238] Methyl 3-hydroxy-5-(methylthio)isothiazole-4-carboxylate

[0239] 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 dimethyl 2-(mercapto(methylthio)methylene)malonate (I005) was added dropwise. The reaction mixture was stirred at 25°C overnight. The acetonitrile was removed from the reaction system by concentration under reduced pressure. The pH of the reaction system was adjusted to 1 with concentrated hydrochloric acid, and a solid was obtained by filtration. The solid was washed with water (20 mL) and EA / PE (10:1, 20 mL), and dried to afford methyl 3-hydroxy-5-(methylthio)isothiazole-4-carboxylate (I006) (4.7 g, yellow solid) in a two-step yield of 76%.

[0240] MS-ESI calculated value [M+H] + 206.3, measured 205.9.

[0241] 1 H NMR (400MHz, DMSO-d6) δ = 11.90 (brs, 1H), 3.76 (s, 3H), 2.56 (s, 3H)

[0242] Step 5

[0243] methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate

[0244] Methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate

[0245] 3-Hydroxy-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I006 (3.7 g, 18.0 mmol) and triethylamine (2.4 g, 23.5 mmol) were dissolved in DCM (30 mL) and, under N protection, cooled to 0° C. Ethyl chloroformate (2.3 g, 21.6 mmol) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and anhydrous acetonitrile (40 mL) was added. The solution was concentrated under reduced pressure to remove dichloromethane to obtain a solution of 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylic acid methyl ester I007 in acetonitrile, which was used directly in the next step.

[0246] Step 6

[0247] methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0248] Methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0249] Under N2 protection, an acetonitrile solution of methyl 3-((ethoxycarbonyl)oxy)-5-(methylthio)isothiazole-4-carboxylate I007 was cooled to 0°C, urea peroxide (4.6 g, 50.5 mmol) was added, and trifluoroacetic anhydride (10.6 g, 50.5 mmol) was added dropwise. The reaction solution was stirred at 0°C for 30 minutes. The reaction solution was quenched with sodium bisulfite (3.8 g, 36.1 mmol) and water (40 mL). The acetonitrile was removed by pressure concentration, and the aqueous solution was extracted with dichloromethane (30 mL x 2). The organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. Methanol (50 mL) was added and the dichloromethane was removed by concentration under reduced pressure to obtain a methanol solution of methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I008, which was used directly in the next step.

[0250] Step 7

[0251] methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate

[0252] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate

[0253] A methanol solution of methyl 3-((ethoxycarbonyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I008 was cooled to 0°C, and a 98% aqueous solution (40 mL) of concentrated sulfuric acid (20 mL) was added dropwise to the reaction system. The reaction solution was stirred and reacted at 60°C overnight. Methanol was removed by concentration under reduced pressure, and the mixture was extracted with dichloromethane (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 obtain a crude product. The crude product was slurried with n-hexane (50 mL) to obtain methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (3.1 g, yellow solid). The three-step yield was 74%.

[0254] MS-ESI calculated value [M+H] + 238.0, measured 237.8.

[0255] 1 H NMR (400MHz, DMSO-d6) δ = 13.07 (brs, 1H), 3.86 (s, 3H), 3.57 (s, 3H).

[0256] Step 8

[0257] methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0258] Methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0259] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (400 mg, 1.7 mmol) and potassium carbonate (345 mg, 2.5 mmol) were dissolved in DMSO (10 mL), and methyl (1-methyl-1H-indazol-3-yl)-4-methylbenzenesulfonate I003 (537 mg, 1.7 mmol) was added. The reaction system was stirred at 25°C overnight. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I010 (350 mg, white solid) in a yield of 54%.

[0260] MS-ESI calculated value [M+H] +382.1, measured 381.9.

[0261] 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).

[0262] Step 9

[0263] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0264] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0265] Methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 65°C overnight. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified using a chromatography column (PE:EA = 1:1) to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate I011 (310 mg, yellow solid) in a yield of 93%.

[0266] MS-ESI calculated value [M+H] + 469.2, measured 469.0.

[0267] 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).

[0268] Step 10

[0269] methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate

[0270] 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0271] 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), and DDQ (446 mg, 2.0 mmol) was added. The reaction system was stirred at 0°C for 30 minutes. The reaction solution was washed with saturated sodium bicarbonate (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain methyl 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylate I012 (150 mg, yellow solid) in a yield of 96%.

[0272] MS-ESI calculated value [M+H] + 319.1, measured 319.0.

[0273] Step 11

[0274] methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0275] Methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0276] 4-(Pyrrolidin-1-yl)butan-1-amine (100 mg, 0.7 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (113 mg, 0.7 mmol) was added, and the reaction was stirred at 0°C for 40 minutes. The reaction was continued to stir at 25°C for 30 minutes. DMSO (5 mL) was added, and THF was removed under reduced pressure. 5-amino-3-((1-methyl-1H-indazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I012 (150 mg, 0.5 mmol) and potassium carbonate (318 mg, 1.0 mmol) were added, and the reaction system was stirred at 25°C overnight. Water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I013 (170 mg, yellow solid), yield: 70%.

[0277] MS-ESI calculated value [M+H] + 487.2, measured 487.0.

[0278] 1 H NMR (400MHz, DMSO-d6) δ = 10.40 (brs, 1H), 8.32 (t, J = 4.2Hz, 1H), 7.89 (d, J = 8.0Hz ,1H),7.63(d,J=8.8Hz,1H),7.44-7.39(m,1H),7.16(d,J=7.6Hz,1H),5.65(s,2H ),4.03(s,3H),3.74(s,3H),3.57-3.40(m,2H),3.19-3.14(m,2H),3.12-3.02(m,2H),2.90-2.87(m,2H),2.06-1.80(m,4H),1.66-1.62(m,2H),1.54-1.47(m,2H). Step 12

[0279] 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0280] 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0281] In a microwave oven, methyl 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I013 (170 mg, 0.35 mmol) was dissolved in anhydrous THF (1 mL), and ammonia methanol (7N, 4 mL) was added. The mixture was stirred at 50°C for 96 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by high-performance preparative chromatography (NaHCO3) to give 3-((1-methyl-1H-indazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T002 (80 mg, white solid) in a yield of 49%.

[0282] MS-ESI calculated value [M+H] + 472.2, measured 472.2.

[0283] 1 H NMR (400MHz, DMSO-d6) δ=10.99(s,1H),8.18(t,J=4.4Hz,1H),7.85(d,J=8.4Hz,1H),7.65(d,J=8.8Hz,1H),7.55(s,1H),7.43(t,J=8.4Hz,1H ),7.17(t,J=8.0Hz,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).

[0284] Example 2: Synthesis of Compound T003

[0285] The synthetic route is as follows:

[0286] first step

[0287] methyl 3-(2-bromoethoxy)benzoate

[0288] Methyl 3-(2-bromoethoxy)benzoate

[0289] Under N2 protection, methyl 3-hydroxybenzoate (10.0 g, 65.8 mmol) was dissolved in acetone (150 mL), and 1,2-dibromoethane (74.2 g, 0.39 mol) and potassium carbonate (18.2 g, 0.13 mol) were added. The mixture was stirred and reacted at 80°C overnight. Water (150 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL x 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain methyl 3-(2-bromoethoxy)benzoate I014 (6.1 g, colorless liquid) in a yield of 36%.

[0290] 1 H NMR (400MHz, CDCl3) δ = 7.59 (d, J = 7.2Hz, 1H), 7.49 (dd, J = 2.0, 2.8Hz, 1H), 7.28 (t, J = 8. 4Hz, 1H), 7.06-7.04 (m, 1H), 4.26 (t, J = 6.0Hz, 2H), 3.84 (s, 3H), 3.58 (t, J = 6.0Hz, 2H).

[0291] Step 2

[0292] methyl 3-(vinyloxy)benzoate

[0293] Methyl 3-(vinyloxy)benzoate

[0294] Under N₂ protection, methyl 3-(2-bromoethoxy)benzoate I014 (3.0 g, 11.6 mmol) was dissolved in anhydrous THF (20 mL), and a 1 M solution of potassium tert-butoxide in tetrahydrofuran (23 mL, 23.2 mmol) was added. The mixture was stirred at room temperature overnight. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 3-(vinyloxy)benzoate I015 (1.7 g, colorless liquid) in an 82% yield.

[0295] Step 3

[0296] methyl 3-cyclopropoxybenzoate

[0297] Methyl 3-cyclopropyloxybenzoate

[0298] Under N₂ protection, methyl 3-(vinyloxy)benzoate I015 (1.7 g, 9.6 mmol) was dissolved in anhydrous DCM (20 mL). Diiodomethane (10.2 g, 38.2 mmol) was added, and the mixture was cooled to 0°C. Diethylzinc (19 mL, 19.1 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. 1N dilute hydrochloric acid (20 mL) was added to the reaction solution, and the layers were separated. The aqueous phase was extracted with DCM (20 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford methyl 3-cyclopropyloxybenzoate I016 (1.1 g crude, colorless liquid), which was used directly in the next step.

[0299] Step 4

[0300] (3-cyclopropoxyphenyl)methanol

[0301] (3-Cyclopropylphenyl)methanol

[0302] Under N2 protection, methyl 3-cyclopropyloxybenzoate I016 (1.1 g, 6.8 mmol) was dissolved in anhydrous THF (10 mL). LAH (327 mg, 8.6 mmol) was added in an ice-water bath, and 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 and filtered through celite. The solid was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified using a chromatography column (PE:EA = 8:1) to obtain (3-cyclopropylphenyl)methanol I017 (870 mg, colorless liquid) in a yield of 92%.

[0303] MS-ESI calculated value [M-OH] + 147.2, measured 147.0.

[0304] 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).

[0305] Step 5

[0306] 3-cyclopropoxybenzyl 4-methylbenzenesulfonate

[0307] 3-Cyclopropyloxybenzyl 4-methylbenzenesulfonate

[0308] (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 temperature was lowered to 0°C under N2 protection, and TsCl (1.3 g, 6.8 mmol) was added. The reaction system was stirred at 0°C for 2 hours. The reaction solution was washed sequentially with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified using a chromatography column (PE:EA = 10:1) to obtain 3-cyclopropyloxybenzyl 4-methylbenzenesulfonate I018 (481 mg, colorless liquid) in a yield of 29%.

[0309] Step 6

[0310] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0311] Methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0312] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (235 mg, 1.0 mmol) and potassium carbonate (410 mg, 3.0 mmol) were dissolved in DMSO (5 mL), and 3-cyclopropyloxybenzyl 4-methylbenzenesulfonate I018 (537 mg, 1.7 mmol) was added. The reaction system was stirred at 25°C overnight. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL x 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I019 (210 mg, yellow solid) in a yield of 55%.

[0313] MS-ESI calculated value [M+H] + 384.1, measured 383.8.

[0314] 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).

[0315] Step 7

[0316] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0317] Methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0318] Methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-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 system was stirred at 60°C overnight. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified using a chromatography column (PE:EA = 5:1) to obtain methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I020 (182 mg, yellow solid) in a yield of 68%.

[0319] MS-ESI calculated value [M+H] + 471.1, measured 470.9.

[0320] Step 8

[0321] methyl 5-amino-3-((3-cyclopropoxybenzyl)oxy)isothiazole-4-carboxylate

[0322] 5-amino-3-((3-cyclopropyloxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0323] 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 / H2O (5 / 1 mL), and DDQ (327 mg, 1.4 mmol) was added. The reaction system was stirred at 0°C for 30 minutes. DCM (15 mL) was added to the reaction solution, and the mixture was washed with saturated sodium bicarbonate solution (15 mL) and saturated brine (15 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 = 4:1) to obtain methyl 5-amino-3-((3-cyclopropyloxybenzyl)oxy)isothiazole-4-carboxylate I021 (110 mg, yellow solid) in a yield of 94%.

[0324] MS-ESI calculated value [M+H] + 321.0, measured 320.9.

[0325] Step 9

[0326] methyl 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0327] 3-((3-cyclopropyloxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0328] 4-(Pyrrolidin-1-yl)butan-1-amine (66 mg, 0.5 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (76 mg, 0.5 mmol) was added, and the reaction was stirred at 0°C for 40 minutes. The reaction was continued to stir at 25°C for 30 minutes. DMSO (5 mL) was added, and THF was removed under reduced pressure. 5-amino-3-((3-cyclopropyloxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I021 (100 mg, 0.3 mmol) and potassium carbonate (86 mg, 0.6 mmol) were added, and the reaction system was stirred at 25°C overnight. Water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I022 (120 mg, white solid), yield: 79%.

[0329] MS-ESI calculated value [M+H] + 489.2, measured 489.0.

[0330] 1 H NMR (400MHz, DMSO-d6) δ = 10.41 (brs, 1H), 8.43 (t, J = 4.2Hz, 1H), 7.30 (t, J = 8.0Hz, 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).

[0331] Step 10

[0332] 3-((3-cyclopropoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0333] 3-((3-cyclopropyloxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0334] In a microwave oven, methyl 3-((3-cyclopropyloxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I022 (120 mg, 0.2 mmol) was dissolved in anhydrous THF (2 mL). Ammonia methanol (7N, 6 mL) was added, and the mixture was stirred at 50°C for 96 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by high-performance preparative chromatography (NaHCO3) to give 3-((3-cyclopropyloxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T003 (120 mg, white solid) in a yield of 59%.

[0335] MS-ESI calculated value [M+H] + 474.2, measured 474.2.

[0336] 1H NMR (400MHz, DMSO-d6) δ = 8.16 (s, 1H), 7.62 (s, 1H), 7.31 (t, J = 8.0Hz, 1H), 8.17-8.14 (m, 1H), 7.10-7.00 (m, 3H), 5.38 (s, 2H), 3.8 3-3.79(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).

[0337] Example 3: Synthesis of Compound T004

[0338] The synthetic route is as follows:

[0339] first step

[0340] methyl 1-methyl-1H-indazole-4-carboxylate

[0341] 1-Methyl-1H-indazole-4-carboxylic acid methyl ester

[0342] Under N2 protection, methyl 1H-indazole-4-carboxylate (2.0 g, 11.4 mmol) was dissolved in DMF (15 mL). 60% sodium hydride (684 mg, 17.1 mmol) was added in an ice-water bath. The mixture was stirred in an ice-water bath for 30 minutes, followed by the addition of iodomethane (2.4 g, 17.1 mmol). The mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with ice water (50 mL), and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain methyl 1-methyl-1H-indazole-4-carboxylate I023 (1.2 g, white solid) in a yield of 55%.

[0343] MS-ESI calculated value [M+H] + 472.2, measured 472.2.

[0344] 1 H NMR (400MHz, DMSO-d6) δ = 8.47 (d, J = 0.8Hz, 1H), 7.92 (dd, J = 0.4, 6.4Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.44 (dd, J = 7.2, 7.4Hz, 1H), 4.11 (s, 3H), 4.01 (s, 3H).

[0345] Step 2

[0346] (1-methyl-1H-indazol-4-yl)methanol

[0347] (1-Methyl-1H-indazol-4-yl)methanol

[0348] Under N2 protection, 1-methyl-1H-indazole-4-carboxylic acid methyl ester I023 (1.3 g, 6.8 mmol) was dissolved in anhydrous THF (15 mL), and LAH (312 mg, 8.2 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 and filtered through celite. The solid was washed with ethyl acetate (20 mL). The filtrate was concentrated under reduced pressure to give (1-methyl-1H-indazol-4-yl)methanol I024 (900 mg, colorless liquid) in a yield of 82%.

[0349] MS-ESI calculated value [M+H] + 163.1, measured 163.0.

[0350] Step 3

[0351] (1-methyl-1H-indazol-4-yl)methyl 4-methylbenzenesulfonate

[0352] Methyl (1-methyl-1H-indazol-4-yl)-4-methylbenzenesulfonate

[0353] (1-Methyl-1H-indazol-4-yl)methanol I024 (900 mg, 5.6 mmol), triethylamine (1.1 g, 11.2 mmol), and DMAP (68 mg, 0.6 mmol) were dissolved in DCM (15 mL). The temperature was lowered to 0°C under N2 protection, and TsCl (1.3 g, 6.7 mmol) was added. The reaction system was stirred at 0°C for 2 hours. The reaction solution was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain (1-methyl-1H-indazol-3-yl) 4-methylbenzenesulfonic acid methyl ester I025 (400 mg, white solid) in a yield of 32%.

[0354] Step 4

[0355] methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0356] Methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0357] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (400 mg, 1.7 mmol) and potassium carbonate (466 mg, 3.38 mmol) were dissolved in DMSO (10 mL), and methyl (1-methyl-1H-indazol-4-yl)-4-methylbenzenesulfonate I025 (537 mg, 1.7 mmol) was added. The reaction system was stirred at 25°C overnight. Water (30 mL) was added to the reaction solution, and the mixture was 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 obtain a crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to obtain methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I026 (410 mg, white solid) in a yield of 63%.

[0358] MS-ESI calculated value [M+H] + 382.1, measured 381.9.

[0359] 1 H NMR (400MHz, DMSO-d6) δ = 8.21 (s, 1H), 7.44-7.42 (m, 2H), 7.26-7.24 (m, 1H), 4.14 (s, 3H), 3.99 (s, 3H), 3.52 (s, 3H).

[0360] Step 5

[0361] methyl methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0362] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0363] Methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 65°C overnight. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified using a chromatography column (PE:EA = 1:1) to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate I027 (450 mg, yellow solid) in a yield of 72%.

[0364] MS-ESI calculated value [M+H] + 469.2, measured 469.0.

[0365] Step 6

[0366] methyl 5-amino-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate

[0367] 5-amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0368] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate 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 system was stirred at 0°C for 30 minutes. The reaction solution was washed with saturated aqueous sodium bicarbonate (15 mL) and saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain methyl 5-amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylate I028 (240 mg, yellow solid) in a yield of 84%.

[0369] MS-ESI calculated value [M+H] + 319.1, measured 319.0.

[0370] Step 7

[0371] methyl3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0372] Methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0373] 4-(Pyrrolidin-1-yl)butan-1-amine (170 mg, 1.2 mmol) was dissolved in anhydrous THF (5 mL), and the temperature was lowered to 0°C under N2 protection. CDI (194 mg, 1.2 mmol) was added, and the reaction was stirred at 0°C for 40 minutes. The reaction was continued at 25°C for 30 minutes, DMSO (5 mL) was added, and THF was removed under reduced pressure. 5-amino-3-(((1-methyl-1H-indazol-4-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I028 (240 mg, 0.8 mmol) and potassium carbonate (221 mg, 1.6 mmol) were added. ol), the reaction system was stirred at 25 ° C overnight. Water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated brine (60 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM:MeOH = 10:1) to give methyl 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I029 (210 mg, yellow solid) in a yield of 57%.

[0374] MS-ESI calculated value [M+H] + 487.2, measured 487.0.

[0375] 1H NMR (400MHz, DMSO-d6) δ = 10.41 (brs, 1H), 8.36 (t, J = 4.2Hz, 1H), 8.19 (d, J = 0.8Hz, 1H), 7.59 (d, J = 8.0Hz, 1H),7.40-7.36(m,1H),7.20(d,J=6.8Hz,1H),5.67(s,2H),4.05(s,3H),3.81(s,3H),3.48-3.40(m,2H), 3.19-3.07 (m, 2H), 3.01-2.96 (m, 2H), 2.94-2.85 (m, 2H), 1.92-1.84 (m, 4H), 1.71-1.62 (m, 2H), 1.54-1.47 (m, 2H). Step 8

[0376] 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0377] 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0378] In a microwave oven, 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 ammonia methanol (7N, 6 mL) was added. The mixture was stirred at 50°C for 96 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by high-performance preparative chromatography (NaHCO3) to give 3-((1-methyl-1H-indazol-4-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T004 (120 mg, white solid) in a yield of 59%.

[0379] MS-ESI calculated value [M+H] + 472.2, measured 472.2.

[0380] 1H NMR (400MHz, DMSO-d6) δ=11.01(s,1H),8.19-8.16m,2H),7.64(d,J=8.4Hz,1H),7.58(s,1H),7.39(t,J=7.2Hz,1H),7.22(d,J= 7.2Hz,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).

[0381] Example 4: Synthesis of Compound T005

[0382] The synthetic route is as follows:

[0383] first step

[0384] 5-bromo-2-(bromomethyl)pyridine

[0385] 5-Bromo-2-(bromomethyl)pyridine

[0386] (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 approximately 16 hours. The reaction solution was poured into water (60 mL) and extracted with ethyl acetate (60 mL x 3). The organic phases were combined and washed sequentially 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 the crude product 5-bromo-2-(bromomethyl)pyridine I030 (4 g, crude) as a red oily liquid.

[0387] The product was confirmed by LCMS.

[0388] Step 2

[0389] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0390] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0391] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (2 g, 8.4 mmol) and potassium carbonate (2.3 g, 16.8 mmol) were dissolved in DMSO (30 mL), and 5-bromo-2-(bromomethyl)pyridine I030 (2.3 g, 9.2 mmol) was added. The reaction system was stirred at 25°C for 5 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 5 / 1-2 / 1) to obtain methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I031 (2 g, 58.8% yield) as a white solid.

[0392] The product was confirmed by LCMS.

[0393] Step 3

[0394] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0395] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0396] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I031 (2 g, 4.9 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (8.2 g, 49 mmol) was added. The reaction system was stirred at 65°C overnight. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was purified using a chromatography column (PE / EA = 10 / 1 to 5 / 1) to obtain methyl 3-((5-bromopyridin-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I032 (2.5 g, crude) as a yellow oily liquid.

[0397] The product was confirmed by LCMS.

[0398] Step 4

[0399] methyl 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylate

[0400] 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0401] 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), and DDQ (4.6 g, 20.4 mmol) was added. The reaction system was stirred at 0°C for 30 minutes. The reaction solution was washed sequentially with saturated aqueous sodium bicarbonate (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified using a chromatography column (PE / EA = 5 / 1-3 / 1) to obtain methyl 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylate I033 (1.3 g, 74.7% yield) as a yellow solid.

[0402] The product was confirmed by LCMS.

[0403] Step 5

[0404] methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0405] Methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0406] 4-(Pyrrolidin-1-yl)butan-1-amine (170 mg, 1.2 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C, CDI (194 mg, 1.2 mmol) was added, and the reaction was stirred at 0°C for 40 minutes. The reaction was continued at 25°C with stirring for 30 minutes. DMSO (5 mL) was added, and THF was removed under reduced pressure. 5-amino-3-((5-bromopyridin-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I033 (1.3 g, 3.8 mmol) and potassium carbonate (1.1 g, 7.6 mmol) were added, and the reaction system was stirred at 25°C overnight. Water (50 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography (PE / EA = 1 / 1-1 / 2) to give a 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).

[0407] The product was confirmed by LCMS.

[0408] Step 6

[0409] 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0410] 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0411] In a microwave oven, methyl 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I034 (300 mg, 0.59 mmol) was dissolved in NH3 / MeOH (4 mL, 13 mol / L), and the mixture was stirred at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance preparative chromatography to afford 3-((5-bromopyridin-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T005 (29 mg, 10% yield) as a white solid.

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

[0413] 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).

[0414] 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.

[0415] Example 5: Synthesis of Compound T006

[0416] The synthetic route is as follows:

[0417] first step

[0418] methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0419] Methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0420] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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. Water (30 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography (PE / EA = 10 / 1 to 2 / 1) to give a yellow solid product, methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I036 (0.5 g, 30.6% yield).

[0421] The product was confirmed by LCMS and H-NMR.

[0422] 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).

[0423] Step 2

[0424] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0425] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0426] Methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 60°C for 1 hour. 1N 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 the crude product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I037 (0.6 g, 98.0% yield), as a white solid.

[0427] The product was confirmed by LCMS and H-NMR.

[0428] 1 H 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, 2 H), 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).

[0429] Step 3

[0430] methyl 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0431] 5-Amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0432] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I037 (0.6 g, 1.26 mmol) was dissolved in DCM / H₂O (6 / 0.6 mL). DDQ (0.57 g, 2.53 mmol) was added portionwise, and the reaction system 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 sequentially 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 using a chromatography column (PE / EA = 10 / 1 to 2 / 1) to obtain methyl 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I038 (0.35 g, 85.3% yield) as a yellow solid.

[0433] The product was confirmed by LCMS and H-NMR.

[0434] 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).

[0435] Step 4

[0436] methyl 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0437] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0438] 4-(Pyrrolidin-1-yl)butan-1-amine (230 mg, 1.62 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C, CDI (262 mg, 1.62 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. DMSO (5 mL) was added, and THF was removed under reduced pressure. 5-amino-3-((3,5-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I038 (350 mg, 1.08 mmol) and potassium carbonate (298 mg, 2.16 mmol) were added, and the reaction system was stirred at 25°C for 16 hours. Water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (10 mL) and saturated brine (20 mL) in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to give a colorless liquid product, 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I039 (300 mg, 56.4% yield).

[0439] The product was confirmed by LCMS and H-NMR.

[0440] 1 H NMR (400MHz, CDCl3) δ: 10.43 (s, 1H), 6.67 (d, 2H, J = 2.0Hz), 6.41 (t, 1H, J = 2.0Hz), 5.41 (s, 2H), 3.91 (s, 3H), 3.82 (s, 6 H), 3.39 (t, 2H, J = 2.0Hz), 3.08 (s, 3H), 2.94 (t, 2H, J = 7.2Hz), 2.06-2.11 (m, 5H), 1.89-1.93 (m, 2H), 1.69-1.72 (m, 2H).

[0441] Step 5

[0442] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0443] 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0444] In a microwave oven, 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). The mixture was stirred at 60°C for 48 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by high-performance preparative chromatography (DCM / MeOH = 10 / 1, 0.1% NH3.H2O) to give 3-((3,5-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T006 (50 mg, 17.2% yield) as a white solid.

[0445] The product was confirmed by LCMS, H-NMR and C-NMR.

[0446] 1 H NMR (400MHz, CDCl3) δ: 10.97 (br s, 1H), 7.80 (br s, 1H), 7.20 (s, 1H), 6.59 (d, 2H, J = 2.0Hz), 6.46 (t, 1H, J = 2.4Hz), 5.87 (br s,1H),5.40(s,2H),3.81(s,6H),3.32-3.34(m,2H),2.63-2.73(m,6H),1.91(s,4H),1.68-1.74(m,4H).

[0447] 13 C NMR (100MHz, 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.

[0448] Example 6: Synthesis of Compound T007

[0449] The synthetic route is as follows:

[0450] first step

[0451] 5-(bromomethyl)benzo[d][1,3]dioxole

[0452] 5-(Bromomethyl)benzo[d][1,3]dioxole

[0453] (2H-1,3-Benzodioxol-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 system was stirred at -40°C for approximately 20 minutes. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 5-(bromomethyl)benzo[d][1,3]dioxol I040 (2 g, 70.8% yield) as a white solid.

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

[0455] 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).

[0456] Step 2

[0457] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0458] 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0459] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (1.1 g, 4.64 mmol) and potassium carbonate (1.28 g, 9.27 mmol) were dissolved in DMSO (10 mL), and 5-(bromomethyl)benzo[d][1,3]dioxole I040 (1.0 g, 4.64 mmol) was added. The reaction system was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was stirred in MTBE (20 mL) for 20 minutes, filtered, and the filter cake was dried to give a yellow solid product 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester I041 (0.85 g, 49.4% yield).

[0460] The product was confirmed by LCMS and H-NMR.

[0461] 1 H NMR (400MHz, CDCl3) δ: 6.92-6.95 (m, 2H), 6.80 (d, 1H, J = 8.0Hz), 5.97 (s, 2H), 5.38 (s, 2H), 3.94 (s, 3H), 3.47 (s, 3H).

[0462] Step 3

[0463] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0464] 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester

[0465] Methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I041 (0.85 g, 2.29 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (3.83 g, 22.9 mmol) was added. The reaction system was stirred at 60°C for 1 hour. Water (20 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 sequentially with 1N HCl (10 mL x 2) and saturated brine (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the crude product, methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I042 (1 g, 95.3% yield), as a yellow solid.

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

[0467] 1 H NMR (400MHz, CDCl3) δ: 8.14 (t, 1H, J = 5.6Hz), 7.18 (d, 1H, J = 8.0Hz), 7.00 (s, 1H), 6.92-6.94 (m, 1H), 6.81 (d, 1H) ,J=8.0Hz),6.45-6.50(m,2H),5.97(s,2H),5.34(s,2H),4.29(d,1H,J=6.0Hz),3.87(s,3H),3.82-3.83(m,6H).

[0468] Step 4

[0469] methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate

[0470] 5-Amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylic acid methyl ester

[0471] Methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I042 (1.0 g, 2.18 mmol) was dissolved in DCM / H₂O (10 / 1 mL). DDQ (0.99 g, 4.36 mmol) was added portionwise at 0°C. The reaction system 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 with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product. The crude product was purified using a chromatography column (PE / EA = 10 / 1 to 2 / 1) to afford methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate I043 (0.4 g, 59.5% yield) as a yellow solid.

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

[0473] 1 H NMR (400MHz, 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).

[0474] Step 5

[0475] methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0476] 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0477] 4-(Pyrrolidin-1-yl)butan-1-amine (277 mg, 1.95 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (316 mg, 1.95 mmol) was added and the reaction was stirred at room temperature for 30 minutes. DMSO (5 mL) was added and THF was removed under reduced pressure. Methyl 5-amino-3-(benzo[d][1,3]dioxol-5-ylmethoxy)isothiazole-4-carboxylate I043 (400 mg, 1.30 mmol) and potassium carbonate (359 mg, 2.59 mmol) were added and the reaction system was stirred at 25°C for 16 hours. Water (15 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (10 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography (DCM / MeOH = 10 / 1) to give a yellow liquid product 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I044 (500 mg, 80.9% yield).

[0478] The product was confirmed by LCMS and H-NMR.

[0479] 1 H NMR(400MHz,CDCl3)δ:10.27(br s,1H),8.10(br s,1H),7.00(s,1H),6.94(d,2H,J=7.6Hz),6.81(d,1H,J=8.0Hz),5.98(s,2H),5.35(s,2H),3 .88(s,3H),3.34(s,2H),2.75(s,4H),2.65(t,2H,J=6.0Hz),1.95(s,4H),1.70-1.75(m,4H).

[0480] Step 6

[0481] 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0482] 3-(Benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0483] In a microwave oven, methyl 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I044 (200 mg, 0.42 mmol) was dissolved in NH3 / MeOH (4 mL, 13 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, which was purified by high-performance preparative chromatography to afford 3-(benzo[d][1,3]dioxol-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T007 (40 mg, 20.6% yield) as a white solid.

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

[0485] 1 H NMR (400MHz, DMSO-d6) δ: 11.01 (s, 1H), 8.20 (s, 1H), 7.61 (s, 1H), 7.11 (d, 1H, J = 1.2Hz), 6.98-7.02 (m, 2H), 6.92 ( d,1H,J=8.0Hz),6.03(s,2H),5.29(s,2H),3.11-3.13(m,2H),2.38-2.41(m,6H),1.66-1.67(m,4H),1.46(s,4H).

[0486] 13 C NMR(100MHz,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.

[0487] Example 7: Synthesis of Compound T009

[0488] The synthetic route is as follows:

[0489] first step

[0490] 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole

[0491] 3-(Bromomethyl)-1,5-dimethyl-1H-pyrazole

[0492] (1,5-Dimethyl-1H-pyrazol-3-yl)methanol (2.0 g, 15.9 mmol) was dissolved in DCM (40 mL), the temperature was lowered to 10°C, and PBr3 (6.4 g, 23.8 mmol) was added. The reaction system was stirred at room temperature for approximately 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 reaction solution was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 3-(bromomethyl)-1,5-dimethyl-1H-pyrazole I049 (2.7 g, 90.1% yield) as a pale white solid.

[0493] The product was confirmed by LCMS and H-NMR.

[0494] 1 H NMR (400MHz, CDCl3) δ: 6.09 (s, 1H), 4.46 (s, 2H), 3.77 (s, 3H), 2.26 (s, 3H).

[0495] Step 2

[0496] methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0497] Methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0498] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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 mixed solution was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (50 mL) and saturated brine (50 mL) in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (DCM / MeOH = 20 / 1-10 / 1) to give a yellow solid product, methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I050 (0.6 g, 67.4% yield).

[0499] The product was confirmed by LCMS and H-NMR.

[0500] 1 H 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).

[0501] Step 3

[0502] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0503] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0504] Methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 65°C for 3 hours. After the reaction, 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, washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under pressure to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate I051 (2.5 g, 99.6% yield) as a yellow solid.

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

[0506] 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).

[0507] Step 4

[0508] methyl 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0509] 5-Amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0510] 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), and DDQ (0.94 g, 4.14 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 10 minutes. Water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (10 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by chromatography column (neutral alumina, PE / EA = 5 / 1-3 / 1-1 / 1-1 / 2) to give a yellow solid product 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I052 (0.78 g, 80% yield).

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

[0512] 1 H NMR (400MHz,CDCl3)δ:6.54(s,2H),6.16(s,1H),5.38(s,2H),3.83(s,3H),3.78(s,3H),2.27(s,3H).Step 5

[0513] methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0514] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0515] 4-(Pyrrolidin-1-yl)butan-1-amine (281 mg, 1.97 mmol) was dissolved in anhydrous THF (25 mL). Under N2 protection, the temperature was lowered to 0°C, CDI (448 mg, 2.76 mmol) was added, and the mixture was stirred at room temperature for 60 minutes. DMSO (25 mL) was added, and THF was removed under reduced pressure. 5-amino-3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I052 (780 mg, 2.76 mmol) and potassium carbonate (546 mg, 3.95 mmol) were added, and the reaction system was stirred at 25°C for 16 hours. Water (100 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with water (100 mL) and saturated brine (100 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give a yellow solid product, methyl 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I053 (700 mg, 56.2% yield).

[0516] The product was confirmed by LCMS and H-NMR.

[0517] 1 H NMR(400MHz,CDCl3)δ:10.27(br s,1H),8.15(br s,1H),6.15(s,1H),5.37(s,2H),3.81(s,3H),3.76(s,3H),3.32(t,2H,J=5.6Hz) ,2.66(s,4H),2.58(t,2H,J=6.0Hz),2.26(s,3H),1.89(s,4H),1.68-1.69(m,4H).

[0518] Step 6

[0519] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0520] 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0521] In a microwave oven, methyl 3-((1,5-dimethyl-1H-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 hours. 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 3-((1,5-dimethyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T009 (75 mg, 31% yield) as a white solid.

[0522] The product was confirmed by LCMS, H-NMR and C-NMR.

[0523] 1 H NMR(400MHz,CDCl3)δ:10.91(br s,1H),7.74(br s,1H),6.13(s,1H),5.67(s,1H),5.41(s,2H),3.78(s,3H),3.32(d,2H,J=3 .6Hz),2.50-2.57(m,6H),2.28(s,3H),1.85(s,4H),1.66(d,4H,J=2.0Hz).

[0524] 13 C NMR(100MHz, CDCl3)δ:169.42,165.96,161.88,154.05,146.03,139.62,105.43 ,97.44,64.10,55.87,53.93,40.55,40.53,36.10,28.15,26.66,23.41,11.21.

[0525] Example 8: Synthesis of Compound T013

[0526] The synthetic route is as follows:

[0527] first step

[0528] 2-(bromomethyl)imidazo[1,2-a]pyridine

[0529] 2-(Bromomethyl)imidazo[1,2-a]pyridine

[0530] Dissolve {imidazo[1,2-a]pyridin-2-yl}methanol (1.0 g, 6.7 mmol) in DCM (40 mL), cool to 0°C, add PBr3 (3.6 g, 13.4 mmol), and stir the reaction at room temperature for approximately 12 hours. After completion of the reaction, concentrate under reduced pressure to obtain the crude product 2-(bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude), a white product.

[0531] The product was confirmed by LCMS.

[0532] Step 2

[0533] methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0534] 3-(Imidazolo[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0535] 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). 2-(bromomethyl)imidazo[1,2-a]pyridine I071 (1.0 g, crude) was added, and the reaction system was stirred at room temperature for 4 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was washed sequentially with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product, methyl 3-(imidazole[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I072 (0.9 g, 66.7% yield), as a yellow solid.

[0536] The product was confirmed by LCMS and H-NMR.

[0537] 1 H NMR (400MHz, CDCl3) δ: 8.12 (d, 1H, J = 6.8Hz), 7.71 (s, 1H), 7.62 (d, 1H, J = 9.2Hz) ),7.21-7.23(m,1H),6.82-6.85(m,1H),5.70(s,2H),3.96(s,3H),3.49(s,3H).

[0538] Step 3

[0539] methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0540] 5-((2,4-dimethoxybenzyl)amino)-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylic acid methyl ester

[0541] Methyl 3-(imidazole[1,2-a]pyridine-2-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I072 (0.9 g, 2.4 mmol) was dissolved in THF (20 mL), and 2,4-dimethoxybenzylamine (4.0 g, 24 mmol) was added. The reaction system was stirred at 65°C for 1 hour. After the reaction, the reaction solution was cooled to room temperature and added to cold water (40 mL). The solid was filtered, washed with water (10 mL x 3), and dried to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazole[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate I073 (0.9 g, 81.9% yield) as a white solid.

[0542] The product was confirmed by LCMS and H-NMR.

[0543] 1 H NMR (400MHz, CDCl3) δ: 8.09-8.10 (m, 2H), 7.68 (s, 1H), 7.60 (d, 1H, J = 9.2Hz), 7.17-7.19 (m, 2H), 6.78-6. 79(m,1H),6.44-6.49(m,2H),5.63(s,2H),4.29(d,2H,J=5.6Hz),3.86(s,3H),3.83(s,3H),3.82(s,3H).

[0544] Step 4

[0545] methyl 5-amino-3-(imidazo[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate

[0546] 5-Amino-3-(imidazole[1,2-a]pyridine-2-methoxy)isothiazole-4-carboxylic acid methyl ester

[0547] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-(imidazole[1,2-a]pyridin-2-ylmethoxy)isothiazole-4-carboxylate I073 (0.9 g, 2.0 mmol) was dissolved in DCM / H₂O (25 / 5 mL). DDQ (1.8 g, 8.0 mmol) was added portionwise at 0°C, and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was washed with saturated aqueous sodium bicarbonate (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 methyl 5-amino-3-(imidazole[1,2-a]pyridin-2-methoxy)isothiazole-4-carboxylate I074 (250 mg, 37.3% yield) as a white solid.

[0548] The product was confirmed by LCMS and H-NMR.

[0549] 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).

[0550] Step 5

[0551] methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0552] 3-(Imidazol[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0553] 4-(Pyrrolidin-1-yl)butan-1-amine (125 mg, 0.88 mmol) was dissolved in anhydrous THF (6 mL). Under N2 protection, the temperature was lowered to 0 °C, CDI (143 mg, 0.88 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (6 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-(imidazole[1,2-a]pyridine-2-methoxy)isothiazole-4-carboxylic acid methyl ester I074 (200 mg, 0.64 mmol) and potassium carbonate (177 mg, 1.28 mmol) were added, and the reaction system was stirred at room temperature for 12 hours. After the reaction is complete, water (40 mL) is added to the reaction solution, and the mixed solution is extracted with dichloromethane (20 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give a white solid product 3-(imidazole[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).

[0554] The product was confirmed by LCMS and H-NMR.

[0555] 1 H NMR (400MHz, CDCl3) δ: 10.10 (br s, 1H), 8.20 (br s, 1H), 8.11 (d, 1H, J = 6.8Hz), 7.71 (s, 1H), 7.58-7.60 (m,1H),7.18(t,1H,J=7.2Hz),6.79(t,1H,J=6.8Hz),5.64(s,2H),3.82 (s,3H),3.34(s,2H),2.63-2.73(m,6H),1.94(s,4H),1.71-1.75(m,4H).

[0556] Step 6

[0557] 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0558] 3-(Imidazol[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0559] In a microwave oven, methyl 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-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). The mixture was sealed and reacted at 60°C for 60 hours. The reaction solution was concentrated under reduced pressure to give the crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O = 10 / 1 / 0.1) to give 3-(imidazo[1,2-a]pyridin-2-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T013 (25 mg, 17.1% yield) as a white solid.

[0560] The product was confirmed by LCMS, H-NMR and C-NMR.

[0561] 1 H NMR (400MHz, CD3OD) δ: 8.43 (d, 1H, J = 6.8Hz), 7.98 (s, 1H), 7.54-7.57 (m, 1H), 7.34-7.38 (m, 1H), 6.95 (t, 1H, J = 6 .8Hz), 5.60 (s, 2H), 3.27 (t, 2H, J = 6.4Hz), 2.78 (s, 4H), 2.68-2.72 (m, 2H), 1.88-1.90 (m, 4H), 1.60-1.67 (m, 4H).

[0562] 13 C NMR(100MHz,CD3OD)δ:168.81,165.81,161.82,154.80,145.26,140.40,126.7 4,126.12,115.97,112.79,112.53,63.44,55.11,53.62,27.02,24.21,22.67.

[0563] Example 9: Synthesis of Compound T015

[0564] The synthetic route is as follows:

[0565] first step

[0566] (5-bromothiazol-2-yl)methyl 4-methylbenzenesulfonate

[0567] Methyl (5-bromothiazol-2-yl)-4-methylbenzenesulfonate

[0568] (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). The temperature was lowered to 0°C under N2 protection, and triethylamine (1.04 g, 10.3 mmol) was added dropwise. The reaction system was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined and washed sequentially 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 product was purified by flash chromatography (PE / EA = 20 / 1 to 2 / 1) to obtain the yellow solid product (5-bromothiazol-2-yl)-4-methylbenzenesulfonic acid methyl ester I081 (1.1 g, 61.5% yield).

[0569] The product was confirmed by LCMS and H-NMR.

[0570] 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).

[0571] Step 2

[0572] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0573] Methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0574] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system 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, washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product, methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I082 (1.3 g, 93.3% yield), as a yellow solid.

[0575] The product was confirmed by LCMS and H-NMR.

[0576] 1 H NMR (400MHz, CDCl3) δ: 7.71 (s, 1H), 5.70 (s, 2H), 4.00 (s, 3H), 3.52 (s, 3H).

[0577] Step 3

[0578] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0579] Methyl 3-((5-bromothiazol-2-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0580] Methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 60°C for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature and added to water (20 mL). Extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined and washed sequentially with 1N HCl solution (50 mL) and saturated brine (50 mL). The product was 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)isothiazole-4-carboxylate I083 (1.5 g, 95.3% yield).

[0581] The product was confirmed by LCMS and H-NMR.

[0582] 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).

[0583] Step 4

[0584] methyl 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylate

[0585] 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0586] 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 system was stirred at room temperature for 40 minutes. After complete reaction, water (20 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 brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain methyl 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylate I084 (0.53 g, 47.6% yield) as a yellow solid.

[0587] The product was confirmed by LCMS and H-NMR.

[0588] 1 H NMR(400MHz, DMSO-d6)δ:7.99(s,2H),7.89(s,1H),5.56(s,2H),3.73(s,3H).

[0589] Step 5

[0590] methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0591] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0592] 4-(Pyrrolidin-1-yl)butan-1-amine (245 mg, 1.72 mmol) was dissolved in anhydrous THF (20 mL). Under N2 protection, the temperature was lowered to 0°C, CDI (279 mg, 1.72 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. DMSO (20 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((5-bromothiazol-2-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I084 (430 mg, 1.23 mmol) and potassium carbonate (339 mg, 2.46 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (60 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (60 mL x 3). The organic phase is washed with water (40 mL) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by column chromatography (DCM / MeOH = 30 / 1 to 20 / 1) to give a yellow solid product, 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I085 (650 mg, 82.8% yield).

[0593] The product was confirmed by LCMS and H-NMR.

[0594] 1 H NMR(400MHz,CDCl3)δ:10.25(br s,1H),8.34(br s,1H),7.68(s,1H),5.64(s,2H),3.91(s,3H),3.35(t,2H,J=5.2Hz),2.75(s,4H),2.66(t,2H,J=5.2Hz),1.96(s,4H),1.73-1.77(m,4H).

[0595] Step 6

[0596] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0597] 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0598] In a microwave tube, methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I085 (400 mg, 0.77 mmol) was dissolved in NH3 / MeOH (3 mL, 10 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. 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) to give methyl 3-((5-bromothiazol-2-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate T015 (50 mg, 12.9% yield) as a white solid.

[0599] The product was confirmed by LCMS, H-NMR and C-NMR.

[0600] 1 H NMR (400MHz, DMSO-d6) δ: 11.05 (s, 1H), 8.23 ​​(t, 1H, J = 5.6Hz), 7.92 (s, 1H), 7.68 (s, 1H), 6.14(s,1H),5.66(s,2H),3.13(d,2H,J=5.6Hz),2.47(s,6H),1.68(s,4H),1.47(s,4H).

[0601] 13 C NMR (100MHz, 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.

[0602] Example 10: Synthesis of Compound T017

[0603] The synthetic route is as follows:

[0604] first step

[0605] 4-cyano-2-fluorobenzyl 4-methylbenzenesulfonate

[0606] 4-Cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid

[0607] 3-Fluoro-4-(hydroxymethyl)benzonitrile I088 (2.0 g, 13.2 mmol) and Ts2O (4.32 g, 8.43 mmol) were dissolved in DCM (20 mL). The temperature was lowered to 0°C under N2 protection, and triethylamine (2.68 g, 26.5 mmol) was added dropwise. The reaction system was stirred at room temperature for 4 hours. After complete reaction, the reaction solution was extracted with water (40 mL) and then with dichloromethane. 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 flash column chromatography (PE / EA = 10 / 1 to 2 / 1) to obtain 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (2.1 g, 52.0% yield) as a white solid.

[0608] The product was confirmed by LCMS and H-NMR.

[0609] 1 H NMR (400MHz, CDCl3) δ: 7.83 (d, 2H, J = 8.4Hz), 7.46-7.54 (m, 2H), 7.34-7.39 (m, 3H), 5.17 (s, 2H), 2.49 (s, 3H).

[0610] Step 2

[0611] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0612] Methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0613] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMSO (10 mL), and 4-cyano-2-fluorobenzyl-4-methylbenzenesulfonic acid I089 (1.42 g, 4.64 mmol) was added. The reaction system was stirred at room temperature for 2 hours. After the reaction is complete, water (30 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (10 mL x 3). The organic phases are combined, washed with water (20 mL) and saturated brine (20 mL) in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The product is purified by flash column chromatography (PE / EA = 10 / 1 to 2 / 1) to give a yellow solid product, methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I090 (1.4 g, 89.7% yield).

[0614] The product was confirmed by LCMS and H-NMR.

[0615] 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).

[0616] Step 3

[0617] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0618] Methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0619] Methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 60°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature and added to water (20 mL). Extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow solid product, methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I091 (1.7 g, 98.3% yield).

[0620] The product was confirmed by LCMS and H-NMR.

[0621] 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).

[0622] Step 4

[0623] methyl 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylate

[0624] 5-Amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0625] Methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I091 (1.3 g, 2.84 mmol) was dissolved in DCM / H2O (10 / 2 mL). DDQ (2.58 g, 11.4 mmol) was added portionwise at 0°C, and the reaction system was stirred at room temperature for 2 hours. After the reaction is complete, water (10 mL) is added to the reaction solution, and the mixture is extracted with dichloromethane (10 mL x 3). The organic phase is washed with saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is stirred and dissolved in PE / EA (v / v = 3 / 1, 5 mL), filtered to leave a filter cake, washed with dichloromethane (2 mL), and dried to give a yellow solid product, 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I092 (0.6 g, 68.7% yield).

[0626] The product was confirmed by LCMS and H-NMR.

[0627] 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).

[0628] Step 5

[0629] methyl 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0630] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0631] 4-(Pyrrolidin-1-yl)butan-1-amine (417 mg, 2.93 mmol) was dissolved in anhydrous THF (5 mL) and the temperature was lowered to 0°C under N2 protection. CDI (475 mg, 2.93 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. DMSO (5 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((4-cyano-2-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I092 (600 mg, 1.95 mmol) and potassium carbonate (538 mg, 3.90 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (20 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (15 mL x 3). The organic phase is washed with water (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give a colorless oily liquid product 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I093 (350 mg, 37.7% yield).

[0632] The product was confirmed by LCMS and H-NMR.

[0633] 1 H NMR(400MHz,CDCl3)δ:10.20(br s,1H),8.32(br s,1H),7.74(t,1H,J=7.6Hz),7.50(d,1H,J=8.0Hz),7.37-7.40(m,1H),5.56(s,2H),3.90( s,3H),3.32-3.33(m,2H),2.53-2.59(m,4H),1.90(s,4H),1.78-1.81(m,2H),1.69(s,4H).

[0634] Step 6

[0635] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0636] 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0637] In a microwave oven, 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), and the mixture was stirred at 60°C for 16 hours. 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) to give a white solid. The product was dissolved in acetonitrile (5 mL) with stirring, filtered, and dried to give 3-((4-cyano-2-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T017 (26 mg, 7.7% yield).

[0638] The product was confirmed by LCMS, H-NMR and C-NMR.

[0639] 1 H NMR (400MHz, CD3OD) δ: 7.71 (d, 1H, J = 7.6Hz), 7.59-7.65 (m, 2H), 5.64 (s, 2H), 3.26 (t, 2 H, J=6.4Hz), 2.66 (s, 4H), 2.59 (t, 2H, J=7.6Hz), 1.84-1.87 (m, 4H), 1.58-1.64 (m, 4H).

[0640] 13 C NMR(100MHz,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.

[0641] Example 11: Synthesis of Compound T022

[0642] The synthetic route is as follows:

[0643] first step

[0644] methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate

[0645] 5-Bromo-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester

[0646] Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (10 g, 64 mmol) was dissolved in acetonitrile (50 mL), POBr3 (55 g, 192 mmol) was added, and the temperature was raised to 80°C with stirring for 24 hours. After the reaction was complete, the mixture was poured into water (200 mL), the pH was adjusted to 8 with sodium bicarbonate, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA = 10 / 1) to obtain methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate I099 (5 g, 35.7% yield) as a white solid.

[0647] The product was confirmed by LCMS.

[0648] Step 2

[0649] (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol

[0650] (5-Bromo-1-methyl-1H-pyrazol-3-yl)methanol

[0651] Under nitrogen, methyl 5-bromo-1-methyl-1H-pyrazole-3-carboxylate I099 (2.5 g, 11.4 mmol) was dissolved in dry THF (30 mL) and cooled to 0°C. LiBH4 (14 mL, 28.5 mmol, 2 mol / L) was added and then allowed to warm to room temperature for approximately 12 hours. After complete reaction, the reaction solution was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by flash column chromatography (PE / EA = 2 / 1) afforded (5-bromo-1-methyl-1H-pyrazol-3-yl)methanol I100 (1.5 g, 68.2% yield) as a colorless oily liquid.

[0652] The product was confirmed by LCMS.

[0653] Step 3

[0654] 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole

[0655] 5-Bromo-3-(bromomethyl)-1-methyl-1H-pyrazole

[0656] (5-Bromo-1-methyl-1H-pyrazol-3-yl)methanol I100 (1.5 g, 7.89 mmol) was dissolved in dichloromethane (30 mL). The temperature was lowered to 0°C, PBr3 (3.2 g, 11.9 mmol) was added, and the mixture was allowed to warm to room temperature for 16 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate (50 mL) and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole I101 (1.65 g, crude) as a colorless oily liquid.

[0657] The product was confirmed by LCMS.

[0658] Step 4

[0659] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0660] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0661] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (1.5 g, 6.33 mmol) was dissolved in anhydrous DMF (20 mL). KCO (1.75 g, 12.7 mmol) and 5-bromo-3-(bromomethyl)-1-methyl-1H-pyrazole I101 (1.61 g, 6.33 mmol) were added sequentially at room temperature. The reaction was stirred for approximately 3 hours. After complete reaction, the reaction mixture was added to water (80 mL) and extracted with ethyl acetate. The combined organic phases were washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by flash column chromatography afforded methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I102 (1.35 g, 51.9% yield) as a white solid.

[0662] The product was confirmed by LCMS and H-NMR.

[0663] 1 H NMR(400MHz, DMSO-d6)δ:6.56(s,1H),5.37(s,2H),3.87(s,3H),3.82(s,3H),3.61(s,3H).

[0664] Step 5

[0665] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4- carboxylate

[0666] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0667] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 and stirred at 60°C for approximately 5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (PE / EA = 3 / 1) to obtain methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I103 (1.7 g, 94.4%) as a white solid.

[0668] The product was confirmed by LCMS.

[0669] Step 6

[0670] methyl 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylate

[0671] 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0672] Methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I103 (1.2 g, 2.41 mmol) was dissolved in DCM / H2O (15 / 3 mL), and DDQ (1.0 g, 3.61 mmol) was added portionwise at 0°C. The reaction system was then stirred for 30 minutes. After the reaction was complete, 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 sodium bicarbonate (30 mL), water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (PE / EA = 2 / 1) to give 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I104 (0.45 g, 53.7% yield) as a white solid product.

[0673] The product was confirmed by LCMS.

[0674] Step 7

[0675] methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0676] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0677] 4-(Pyrrolidin-1-yl)butan-1-amine (344 mg, 2.42 mmol) was dissolved in anhydrous THF (5 mL) and cooled to 0°C under N2 protection. CDI (392 mg, 2.42 mmol) was added, followed by stirring for 30 minutes and then stirring at room temperature for 1 hour. DMSO (10 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I104 (600 mg, 1.73 mmol) and potassium carbonate (477 mg, 3.46 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (50 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (20 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by column chromatography (DCM / MeOH = 10 / 1) to give a white solid product 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I105 (600 mg, 67.4% yield).

[0678] The product was confirmed by LCMS.

[0679] Step 8

[0680] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0681] 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0682] In a microwave tube, methyl 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-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 sealed and reacted at 60°C for 16 hours. 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) to give 3-((5-bromo-1-methyl-1H-pyrazol-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T022 (50 mg, 8.6% yield) as a white solid.

[0683] The product was confirmed by LCMS, H-NMR and C-NMR.

[0684] 1 H NMR(400MHz, CDCl3)δ:10.90(s,1H),7.73(s,1H),7.21(s,1H),6.42(s,1H),5.72(s,1H),5.42(s,2H), 3.89(s,3H),3.31-3.32(m,2H),2.47-2.53(m,6H),2.10(s,2H),1.83-1.87(m,4H),1.62-1.65(m,2H).

[0685] 13 C NMR(100MHz, CDCl3)δ:169.60,165.86,161.55,154.02,147.95,113.99,108.59,63.72 ,55.89,53.93,40.78,40.57,37.63,28.35,28.27,28.13,28.02,26.77,23.60,23.41.

[0686] Example 12: Synthesis of Compound T023

[0687] The synthetic route is as follows:

[0688] first step

[0689] methyl3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate

[0690] Methyl 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate

[0691] 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, and the reaction was stirred at 0°C for 0.5 hour and continued to stir at room temperature for 0.5 hour. The reaction solution was poured into water (30 mL), and the mixed solution was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative thin layer chromatography (PE / EA=3 / 1) to give a yellow solid product, methyl 3-((4-bromo-2,6-difluorobenzyloxy)oxy)-5-((5-(4-tert-butoxycarbonyl)piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxylate I107 (22.5 mg, 5% yield).

[0692] The product was confirmed by LCMS and HNMR.

[0693] 1 H NMR (400MHz, CDCl3) δ: 10.80 (s, 1H), 8.11 (d, 1H, J = 2.4Hz), 7.36-7.39 (m, 1H), 7.14-7.18 (m, 2H), 6 .92(d,1H,J=8.8Hz),5.48(s,2H),3.84(s,3H),3.62-3.64(m,4H),3.11-3.13(m,4H),1.52(s,9H).

[0694] Step 2

[0695] tert-butyl4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridine-3-yl)piperazine-1-carboxylate

[0696] tert-Butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

[0697] 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 sealed and reacted at 60°C for 72 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by preparative thin-layer chromatography (PE / EA=3 / 1) to give a yellow solid product, tert-butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate I108 (50.0 mg, 46% yield).

[0698] The product was confirmed by LCMS and H-NMR.

[0699] 1 H NMR (400 MHz, CDCl3) 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). Step 3

[0700] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0701] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(piperazin-1-yl)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0702] Tert-butyl 4-(6-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-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), and the mixture was stirred at 25°C for 1.0 hour. The reaction mixture was concentrated under reduced pressure, and water (10 mL) was added to the residue, and the pH was adjusted to 9.0 with aqueous sodium carbonate. The mixed solution was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative thin layer chromatography (DCM / MeOH = 20 / 1) to give 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 product.

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

[0704] 1 H NMR (400MHz, CDCl3) δ: 11.48 (s, 1H), 8.09 (d, 1H, J = 2.8Hz), 7.34-7.37 (m, 1H), 7.18-7.19 (m, 2H), 7 .02(s,1H),6.93(d,1H,J=8.8Hz),5.56(s,2H),5.31(s,1H),3.13-3.14(m,4H),3.08-3.09(m,4H).

[0705] 13 C NMR(100MHz, CDCl3)δ:168.67,166.37,161.41,144.65,142.87,134.04,128.0 4,115.87,115.78,115.58,111.71,111.34,95.37,57.51,57.47,50.98,46.01.

[0706] Example 13: Synthesis of Compound T024

[0707] The synthetic route is as follows:

[0708] first step

[0709] 6-aminopyridin-3-ol

[0710] 6-Aminopyridin-3-ol

[0711] 5-Methoxypyridin-2-amine (2.8 g, 22.6 mmol) was dissolved in 48% aq. HBr (15 mL), and the reaction system was stirred at reflux for 12 hours. The reaction solution was cooled to room temperature and poured into cold water (20 mL). The pH was adjusted to 7-8 with aqueous sodium carbonate solution, and the product was extracted with ethyl acetate (40 mL x 10). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product 6-aminopyridin-3-ol I109 (1.3 g, 52.3% yield) as a black oil.

[0712] The product was confirmed by LCMS and HNMR

[0713] 1 H NMR (400MHz, CDCl3) δ: 8.62 (s, 1H), 7.50 (dd, 1H, J = 3.2, 0.8Hz), 6.91 (dd, 1H, J = 8.8, 3.2Hz), 6.34

[0714] (dd,1H,J=8.8,0.8Hz),5.19(s,2H).

[0715] Step 2

[0716] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-amine

[0717] 5-(2-Pyrrolidin-1-ylethoxy)pyridin-2-amine

[0718] 6-Aminopyridin-3-ol I109 (1.3 g, 11.8 mmol) was dissolved in DMF (15 mL), and 1-(2-chloroethyl)pyrrolidine hydrochloride (2.0 g, 11.8 mmol) and sodium hydroxide (1.9 g, 47.2 mmol) were added. The reaction system was stirred at 65°C for 2.0 hours. The reaction solution was cooled to room temperature, poured into brine (40 mL), and extracted with DCM / MeOH = 10 / 1 (v / v, 30 mL x 10). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 50 / 1 to 10 / 1) to obtain 5-(2-pyrrolidin-1-ylethoxy)pyridin-2-amine I110 (1.3 g, 53.1% yield) as a black solid.

[0719] The product was confirmed by LCMS and HNMR

[0720] 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),

[0721] 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).

[0722] Step 3

[0723] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-

[0724] carboxylate

[0725] 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester

[0726] To a solution of methyl 3-(4-bromo-2,6-difluorophenoxy)-5-methylsulfonyl-1,2-thiazole-4-carboxylate 1178 (300 mg, 0.68 mmol) and 5-(2-pyrrolidin-1-ylethoxy)pyridin-2-amine 1110 (155 mg, 0.75 mmol) in THF (30 mL) was added LiHMDS (1.4 mL, 1.4 mmol, 1 mol / L) dropwise at 0°C. The reaction was stirred at 0-10°C for 1.0 hour, the reaction solution was poured into aqueous NH4Cl solution (40 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative thin-layer chromatography (DCM / MeOH = 20 / 1) to give 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester I111 (18 mg, 4.8% yield) as a white solid product.

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

[0728] 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).

[0729] Step 4

[0730] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-2-yl)amino)isothiazole-4-carboxamide

[0731] 3-(4-Bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide

[0732] 3-(4-Bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxylic acid methyl ester I111 (110 mg, 0.19 mmol) was dissolved in NH3 / MeOH (5 mL, 10 mol / L) and THF (1 mL). The mixture was sealed 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 obtain a white solid product 3-(4-bromo-2,6-difluorobenzyloxy)-5-(5-(2-pyrrolidin-1-ylethoxy)pyridine-2-aminopyridine-4-carboxamide T024 (21 mg, 19.6% yield).

[0733] The product was confirmed by LCMS, H-NMR and C-NMR.

[0734] 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).

[0735] 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.

[0736] Example 14: Synthesis of Compound T026

[0737] The synthetic route is as follows:

[0738] first step

[0739] 5-(bromomethyl)benzofuran

[0740] 5-(Bromomethyl)benzofuran

[0741] (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 approximately 2 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined and 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 5-(bromomethyl)benzofuran I117 (2.5 g, crude) as a yellow oily liquid.

[0742] The product was confirmed by LCMS.

[0743] Step 2

[0744] methyl 3-(benzofuran-5-ylmethoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0745] 3-(Benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylic acid methyl ester

[0746] 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), and 5-(bromomethyl)benzofuran I117 (1.33 g, 6.33 mmol) was added. The reaction system was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed sequentially 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 methyl 3-(benzofuran-5-methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I118 (1.5 g, 65.2% yield) as a white solid.

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

[0748] 1 H NMR (400MHz, DMSO-d6) δ: 8.03 (d, 1H, J = 1.6Hz), 7.79 (s, 1H), 7.64 (d, 1H, J = 8.4Hz), 7.4 4(dd,1H,J=8.8,1.2Hz),7.00(d,1H,J=1.2Hz),5.58(s,2H),3.88(s,3H),3.61(s,3H).

[0749] Step 3

[0750] methyl 3-(benzofuran-5-ylmethoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0751] 3-(Benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester

[0752] 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. The reaction system was stirred at 65°C for 6 hours. After completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (PE / EA = 5 / 1) to obtain methyl 3-(benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I119 (2.0 g, 81.0% yield) as a yellow solid.

[0753] The product was confirmed by LCMS.

[0754] Step 4

[0755] methyl 5-amino-3-(benzofuran-5-ylmethoxy)isothiazole-4-carboxylate

[0756] 5-Amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester

[0757] Methyl 3-(benzofuran-5-methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I119 (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 minutes. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was washed with saturated aqueous sodium bicarbonate (25 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1) to obtain methyl 5-amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylate I120 (0.45 g, 45% yield) as a yellow solid.

[0758] The product was confirmed by LCMS.

[0759] Step 5

[0760] methyl 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0761] 3-(Benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0762] 4-(Pyrrolidin-1-yl)butan-1-amine (392 mg, 2.76 mmol) was dissolved in anhydrous THF (10 mL). Under N2 protection, the temperature was lowered to 0 ° C. CDI (448 mg, 2.76 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (10 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-(benzofuran-5-methoxy)isothiazole-4-carboxylic acid methyl ester I120 (600 mg, 1.97 mmol) and potassium carbonate (545 mg, 3.95 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (50 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (20 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give a yellow oily liquid product 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I121 (600 mg, 64.4% yield).

[0763] The product was confirmed by LCMS.

[0764] Step 6

[0765] 3-(benzofuran-5-ylmethoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0766] 3-(Benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0767] In a microwave tube, methyl 3-(benzofuran-5-methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I121 (600 mg, 1.27 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. 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) 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.

[0768] The product was confirmed by LCMS, H-NMR and C-NMR.

[0769] 1H NMR (400MHz, CD3OD) δ: 7.78-7.79 (m, 2H), 7.53 (d, 1H, J = 8.8Hz), 7.44 (d, 1H, J = 8.4Hz), 6.87 (d, 1H ,J=1.2Hz),5.54(s,2H),3.25(t,2H,J=6.0Hz),2.49-2.57(m,6H),1.82(s,4H),1.58-1.60(m,4H).

[0770] 13 C NMR(100MHz,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.

[0771] Example 15: Synthesis of Compound T027

[0772] The synthetic route is as follows:

[0773] first step

[0774] 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene

[0775] 4-(Bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene

[0776] [4-(Difluoromethoxy)-3-fluorophenyl]methanol (3.0 g, 15.6 mmol) was dissolved in DCM (50 mL), cooled 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 the reaction was complete, the reaction solution was added to water (50 mL) and extracted with dichloromethane (50 mL x 2). The organic phases were combined and washed sequentially 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 crude product) as a colorless oily liquid.

[0777] The product was confirmed by LCMS.

[0778] Step 2

[0779] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0780] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0781] 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 (20 mL), and 4-(bromomethyl)-1-(difluoromethoxy)-2-fluorobenzene I122 (2.1 g, 8.24 mmol) was added. The reaction system was stirred at room temperature for 5 hours. Water (20 mL) was added to the reaction solution, and the mixed solution was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with water (20 mL) and saturated brine (20 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column chromatography (PE / EA = 3 / 1) to give a white solid product, methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I123 (1.5 g, 57.7% yield).

[0782] The product was confirmed by LCMS and H-NMR.

[0783] 1 H NMR (400MHz, DMSO-d6)δ:7.55(d,1H,J=1.6Hz),7.41-7.45(m,1H),7.36-7.38(m,1H),7.27(t,1H,J=73.2),5.50(s,2H),3.90(s,3H),3.62(s,3H)

[0784] Step 3

[0785] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0786] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[0787] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA = 5 / 1) to obtain methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I124 (2 g, 82.6% yield) as a white solid.

[0788] The product was confirmed by LCMS.

[0789] Step 4

[0790] methyl 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylate

[0791] 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0792] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I124 (2.3 g, 4.62 mmol) was dissolved in DCM / H2O (20 / 4 mL) and DDQ (1.92 g, 6.93 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 20 minutes. After the reaction was complete, water (10 mL) was added to the reaction solution, which was washed with saturated aqueous sodium bicarbonate (25 mL). The organic phase was washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / ) to obtain methyl 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylate I125 (0.6 g, 37.5% yield) as a yellow solid.

[0793] The product was confirmed by LCMS and H-NMR.

[0794] 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)

[0795] Step 5

[0796] methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-

[0797] carboxylate

[0798] Methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0799] 4-(Pyrrolidin-1-yl)butan-1-amine (343 mg, 2.42 mmol) was dissolved in anhydrous THF (10 mL). Under N2 protection, the temperature was lowered to 0 ° C. CDI (491 mg, 2.42 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (10 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I125 (600 mg, 1.72 mmol) and potassium carbonate (476 mg, 3.45 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (40 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (15 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give a yellow oily liquid product 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I126 (600 mg, 69.4% yield).

[0800] The product was confirmed by LCMS.

[0801] Step 6

[0802] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0803] 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0804] In a microwave tube, methyl 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I126 (600 mg, 1.20 mmol) was dissolved in NH3 / MeOH (10 mL, 13 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. 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) to give 3-((4-(difluoromethoxy)-3-fluorobenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T027 (60 mg, 10.3% yield) as a white solid.

[0805] The product was confirmed by LCMS, H-NMR and C-NMR.

[0806] 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).

[0807] 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.

[0808] Example 16: Synthesis of Compound T028

[0809] The synthetic route is as follows:

[0810] first step

[0811] methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0812] Methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0813] 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). 1-(bromomethyl)-3-methoxybenzene I127 (420 mg, 2.1 mol) was added, and 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 filtered and dried to obtain methyl 3-((3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I128 (438 mg, 58.4% yield), a white solid.

[0814] The product was confirmed by LCMS and H-NMR.

[0815] 1 H NMR (400MHz, CDCl3) δ: 7.32 (t, 1H, J = 8.0Hz), 7.03-7.06 (m, 2H), 6.90 (dd, 1H, J = 8.4, 2.0Hz), 5.49 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.50 (s, 3H).

[0816] Step 2

[0817] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0818] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylate

[0819] 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 cooled to room temperature and added to cold water (40 mL). The solid was filtered and dried to obtain a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylate I129 (500 mg, crude product).

[0820] The product was confirmed by LCMS.

[0821] Step 3

[0822] methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0823] 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0824] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-methoxyphenyl)oxy)isothiazole-4-carboxylate I129 (450 mg, 1.mmol) was dissolved in DCM / H₂O (5 / 1 mL). DDQ (920 mg, 4.04 mmol) was added portionwise at 0°C, and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was purified by flash column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain methyl 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylate I130 (200 mg, 67.1% yield) as a white solid.

[0825] The product was confirmed by LCMS.

[0826] Step 4

[0827] methyl 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0828] 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0829] 4-(Pyrrolidin-1-yl)butan-1-amine (102 mg, 0.72 mmol) was dissolved in anhydrous THF (5 mL) and the temperature was lowered to 0°C under N2 protection. CDI (117 mg, 0.72 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (6 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I130 (150 mg, 0.51 mmol) and potassium carbonate (141 mg, 1.02 mmol) were added, and the reaction system was stirred at room temperature for 1 hour. After the reaction is complete, water (5 mL) is added to the reaction solution, and the solid is filtered off. The filter cake is dried to obtain a crude product, which is purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1) to give a yellow solid product, 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I131 (75 mg, 31.8% yield).

[0830] The product was confirmed by LCMS and H-NMR.

[0831] 1 H NMR (400MHz, CDCl3) δ: 10.22 (s, 1H), 8.24 (s, 1H), 7.28-7.32 (m, 1H), 7.04-7.07 (m, 2H), 6.87 (d, 1H, J = 7.6Hz), 5.44 ( s,2H),3.89(s,3H),3.84(s,3H),3.33(s,2H),2.61-2.64(m,4H),2.54-2.56(m,2H),1.90(s,4H),1.26-1.30(m,4H).

[0832] Step 5

[0833] 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0834] 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0835] 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 sealed and reacted at 60°C for 16 hours. 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) to give 3-((3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T028 (15 mg, 15.4% yield) as a white solid.

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

[0837] 1 H NMR(400MHz,CDCl3)δ:10.94(br s,1H),7.82(br s,1H),7.33(t,1H,J=8.0Hz),7.19(s,1H),7.03(d,1H,J=7.6Hz),7.00(d,1H,J=2.4Hz),6.92(dd,1H,J=8.0 ,2.4Hz),5.48(s,1H),5.45(s,2H),3.84(s,3H),3.34(s,2H),2.61-2.69(m,6H),1.92(s,4H),1.71(s,4H).

[0838] 13 C NMR (100MHz, 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.

[0839] Example 17: Synthesis of Compound T029

[0840] The synthetic route is as follows:

[0841] first step

[0842] methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0843] Methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0844] 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). 4-(bromomethyl)-2-fluoro-1-methoxybenzene I132 (462 mg, 2.1 mmol) was added, and the reaction system was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the solid was filtered. After drying the filter cake, the crude product was obtained as a yellow solid, methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I133 (500 mg, 63.2% yield).

[0845] The product was confirmed by LCMS and H-NMR.

[0846] 1 H NMR (400MHz, CDCl3)δ:7.18-7.25(m,2H),6.98(t,1H,J=8.4Hz),5.42(s,2H),3.98(s,3H),3.92(s,3H),3.49(s,3H).

[0847] Step 2

[0848] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0849] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylate

[0850] 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 system was stirred at 60°C for 2 hours. After the reaction, the reaction solution was cooled to room temperature and added to water (40 mL). The solid was filtered and dried to obtain a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylate I134 (550 mg, 77.0% yield).

[0851] The product was confirmed by LCMS.

[0852] Step 3

[0853] methyl 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0854] 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0855] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((3-fluoro-4-methoxyphenyl)oxy)isothiazole-4-carboxylate I134 (500 mg, 1.08 mmol) was dissolved in DCM / H2O (5 / 1 mL). DDQ (983 mg, 4.32 mmol) was added portionwise at 0°C. The reaction system was stirred at 0°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain methyl 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylate I135 (220 mg, 65.1% yield) as a yellow solid.

[0856] The product was confirmed by LCMS.

[0857] Step 4

[0858] methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0859] Methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0860] 4-(Pyrrolidin-1-yl)butan-1-amine (108 mg, 0.76 mmol) was dissolved in anhydrous THF (6 mL) and the temperature was lowered to 0°C under N2 protection. CDI (123 mg, 0.76 mmol) was added and the reaction was stirred at room temperature for 1 hour. DMSO (6 mL) was added and most of the THF was removed under reduced pressure. 5-amino-3-((3-fluoro-4-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I135 (170 mg, 0.54 mmol) and potassium carbonate (149 mg, 1.08 mmol) were added and the reaction system was stirred at room temperature for 1 hour. After the reaction is complete, water (5 mL) is added to the reaction solution, and the solid is filtered and dried to obtain a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH=10 / 1) to give a yellow solid product 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I136 (100 mg, 38.4% yield).

[0861] The product was confirmed by LCMS and H-NMR.

[0862] 1 H NMR (400MHz, CDCl3) δ: 10.25 (s, 1H), 8.24 (s, 1H), 7.25-7.28 (m, 1H,), 7.17 (d, 1H, J = 8.4Hz), 6.97 (t, 1H, J = 8.4Hz), 5.3 7(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).

[0863] Step 5

[0864] 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0865] 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0866] In a microwave tube, methyl 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I136 (140 mg, 0.28 mmol) was dissolved in NH3 / MeOH (3 mL, 9 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. 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) to give 3-((3-fluoro-4-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T029 (15 mg, 11.9% yield) as a white solid.

[0867] The product was confirmed by LCMS, H-NMR and C-NMR.

[0868] 1 H NMR (400MHz, CD3OD) δ: 7.25-7.29 (m, 2H), 7.13 (d, 1H, J = 8.4Hz), 5.40 (s, 2H), 3.90 ( s,3H),3.25-3.32(m,3H),2.56-2.65(m,5H),1.83-1.87(m,4H),1.61-1.62(m,4H).

[0869] 13 C NMR(100MHz,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.

[0870] Example 18: Synthesis of Compound T030

[0871] The synthetic route is as follows:

[0872] first step

[0873] 1-(bromomethyl)-2-fluoro-3-methoxybenzene

[0874] 1-(Bromomethyl)-2-fluoro-3-methoxybenzene

[0875] Dissolve (2-fluoro-3-methoxyphenyl)methanol (0.5 g, 3.2 mmol) in DCM (15 mL) and cool to 0°C. Add PBr3 (1.0 g, 3.8 mmol) under nitrogen. Stir the reaction system at room temperature for approximately 1 hour. After completion of the reaction, concentrate under reduced pressure to obtain the crude product, 1-(bromomethyl)-2-fluoro-3-methoxybenzene I137 (1 g, crude), as a white product.

[0876] The product was confirmed by LCMS.

[0877] Step 2

[0878] methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0879] Methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0880] 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 system was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed sequentially with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I138 (0.7 g, 58.3% yield), as a white solid.

[0881] The product was confirmed by LCMS and H-NMR.

[0882] 1 H NMR(400MHz, 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).

[0883] Step 3

[0884] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0885] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylate

[0886] Methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I138 (0.7 g, 1.9 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (2.2 g, 13.3 mmol) was added. The reaction system was stirred at 60°C for 1 hour. After the reaction, the reaction solution was cooled to room temperature and added to water (40 mL). The solid was filtered, washed with water (10 mL x 3), and dried to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylate I139 (0.6 g, 70.6% yield) as a white solid.

[0887] The product was confirmed by LCMS and H-NMR.

[0888] 1 H NMR(400MHz, CDCl3)δ:8.13(br s,1H),7.15-7.19(m,2H),7.09(t,1H,J=8.0Hz),6.94(t,1H,J=8.0Hz),6.45-6.49(m,2H) ,5.52(s,2H),4.29(d,2H,J=5.6Hz),3.92(s,3H),3.87(s,3H),3.83(s,3H),3.82(s,3H).

[0889] Step 4

[0890] methyl 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate

[0891] 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0892] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-fluoro-3-methoxyphenyl)oxy)isothiazole-4-carboxylate I139 (0.4 g, 0.86 mmol) was dissolved in DCM / H2O (12 / 2.4 mL). DDQ (0.78 g, 3.4 mmol) was added portionwise at 0°C, and the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, 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 methyl 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylate I140 (180 mg, 67.2% yield) as a yellow solid.

[0893] The product was confirmed by LCMS and H-NMR.

[0894] 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).

[0895] Step 5

[0896] methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0897] Methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0898] 4-(Pyrrolidin-1-yl)butan-1-amine (116 mg, 0.82 mmol) was dissolved in anhydrous THF (6 mL). Under N2 protection, the temperature was lowered to 0 ° C. CDI (132 mg, 0.82 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (6 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((2-fluoro-3-methoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I140 (180 mg, 0.58) and potassium carbonate (160 mg, 1.16 mmol) were added, and the reaction system was stirred at room temperature for 8 hours. After the reaction is complete, water (20 mL) is added to the reaction solution, and the mixed solution is extracted with dichloromethane (10 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give a yellow solid product 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I141 (130 mg, 46.8% yield).

[0899] The product was confirmed by LCMS and H-NMR.

[0900] 1 H NMR (400MHz, CDCl3) δ: 10.10 (br, 1H), 7.90 (br, 1H), 7.08-7.15 (m, 2H), 6.94 (d, 1H, J = 1.6Hz), 5.53 (s, 2H), 3. 91(s,3H),3.88(s,3H),3.33(s,2H),2.68(s,4H),2.60(t,2H,J=6.4Hz),1.91-2.00(m,4H),1.68-1.72(m,4H).

[0901] Step 6

[0902] 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0903] 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0904] In a microwave tube, methyl 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I141 (180 mg, 0.37 mmol) was dissolved in NH3 / MeOH (6 mL, 9 mol / L), and the mixture was sealed and reacted at 60°C for 72 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O = 10 / 1 / 0.1) to give 3-((2-fluoro-3-methoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T030 (25 mg, 12.9% yield) as a white solid.

[0905] The product was confirmed by LCMS, H-NMR and C-NMR.

[0906] 1 H NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.20(s,1H),7.64(s,1H),7.14-7.19(m,2H),7.08-7.10(m,1H),6.95 (s,1H),5.47(s,2H),3.85(s,3H),3.12(d,2H,J=5.6Hz),2.37-2.40(m,6H),1.64-1.68(m,4H),1.46(s,4H).

[0907] 13 C NMR (100MHz, 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.

[0908] Example 19: Synthesis of Compound T032

[0909] The synthetic route is as follows:

[0910] first step

[0911] 1-(bromomethyl)-2,3-dimethoxybenzene

[0912] 1-(Bromomethyl)-2,3-dimethoxybenzene

[0913] (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 approximately 1 hour. After complete reaction, the reaction solution was poured into water (40 mL) and extracted with dichloromethane. The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product 1-(bromomethyl)-2,3-dimethoxybenzene I147 (0.6 g, 87.3% yield) as a colorless oily liquid.

[0914] The product was confirmed by LCMS and H-NMR.

[0915] 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).

[0916] Step 2

[0917] methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0918] Methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0919] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-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 system was stirred at room temperature for 1 hour. Water (30 mL) was added to the reaction solution, and the solid was filtered. The filter cake was washed with water and dried to give the crude product, methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I148 (0.6 g, 72.0% yield), as a white solid.

[0920] The product was confirmed by LCMS and H-NMR.

[0921] 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).

[0922] Step 3

[0923] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0924] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0925] Methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-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 system was stirred at 65°C for 1 hour. After the reaction, the reaction solution was added to water (30 mL) and filtered to obtain a solid. The filter cake was washed with water and dried to obtain a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I149 (0.54 g, 88.4% yield).

[0926] The product was confirmed by LCMS and H-NMR.

[0927] 1 H 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 ,1.6Hz,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).

[0928] Step 4

[0929] methyl 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate

[0930] 5-Amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[0931] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I149 (0.6 g, 1.26 mmol) was dissolved in DCM / H₂O (6 / 1.2 mL). DDQ (0.34 g, 1.52 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for half an hour. After the reaction was complete, neutral alumina was added to the reaction solution, and most of the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography (neutral alumina, PE / EA = 10 / 1 to 1 / 1) to obtain methyl 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylate I150 (0.35 g, 85.3% yield) as a white solid.

[0932] The product was confirmed by LCMS and H-NMR.

[0933] 1 H NMR (400MHz, CDCl3) δ: 7.18 (dd, J=7.8, 1.6Hz, 1H), 7.10 (t, J=7.9Hz, 1H), 6.93 (dd, J=8.1,1.6Hz,1H),6.38-6.49(m,2H),5.51(s,2H),3.90-3.91(m,6H),3.85(s,3H).

[0934] Step 5

[0935] methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0936] 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[0937] 4-(Pyrrolidin-1-yl)butan-1-amine (123 mg, 0.86 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0 ° C. CDI (140 mg, 0.86 mmol) was added and the reaction was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-amino-3-((2,3-dimethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I150 (200 mg, 0.62 mmol) and potassium carbonate (170 mg, 1.23 mmol) were added and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution, and the solid was filtered to obtain the solid. The filter cake was washed with water and dried to obtain the crude product as a white solid product 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I151 (200 mg, 65.8% yield).

[0938] The product was confirmed by LCMS and H-NMR.

[0939] 1 H NMR(400MHz,CDCl3)δ:10.22(br s,1H),8.20(br s,1H),7.18(dd,J=7.7,1.6Hz,1H),7.09(t,J=7.9Hz,1H),6.92(dd,J=8.1,1.5Hz,1H),5.52(s,2H),3.90- 3.91(m,6H),3.86(s,3H),3.33(d,J=5.4Hz,2H),2.47-2.63(m,6H),1.84-1.96(m,4H),1.68-1.74(m,4H).

[0940] Step 6

[0941] 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0942] 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[0943] In a microwave tube, methyl 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I151 (200 mg, 0.42 mmol) was dissolved in NH3 / MeOH (14 mL, 10 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. 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 3-((2,3-dimethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T032 (27 mg, 13.9% yield) as a white solid.

[0944] The product was confirmed by LCMS, H-NMR and C-NMR.

[0945] 1 H NMR(400MHz,CDCl3)δ:10.91(br s,1H),7.76(br s,1H),7.25-7.29(m,1H),7.09(t,J=7.8Hz,1H),7.03(dd,J=7.8,1.7Hz,1H),6.96(dd,J=8.0,1.7Hz,1H),5.65(s,1H),5.52( s,2H),3.89-3.90(m,6H),3.26-3.37(m,2H),2.52-2.63(m,4H),2.51(t,2H,J=6.4Hz),1.74-1.92(m,4H),1.58-1.73(m,4H).

[0946] 13 C NMR(100MHz, 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.

[0947] Example 20: Synthesis of Compound T033

[0948] The synthetic route is as follows:

[0949] first step

[0950] 5-(bromomethyl)-2-methoxypyridine

[0951] 5-(Bromomethyl)-2-methoxypyridine

[0952] Dissolve (6-methoxypyridin-3-yl)methanol (0.5 g, 3.6 mmol) in DCM (15 mL), cool to 0°C, add PBr3 (1.1 g, 4.0 mmol), and stir the reaction at room temperature for approximately 4 hours. After completion of the reaction, concentrate under reduced pressure to obtain the crude product 5-(bromomethyl)-2-methoxypyridine I152 (1.0 g, crude) as a yellow solid.

[0953] The product was confirmed by LCMS and used directly in the next reaction.

[0954] Step 2

[0955] methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0956] Methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0957] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (0.85 g, 3.6 mmol) and potassium carbonate (2.0 g, 14.4 mmol) were dissolved in DMF (15 mL). 5-(bromomethyl)-2-methoxypyridine I152 (1.0 g, crude) was added, and the reaction system was stirred at room temperature for 2 hours. Water (50 mL) was added to the reaction solution, and the solid was filtered. The filter cake was washed with water and dried to give the crude product, methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I153 (0.8 g, 61.5% yield), as a white solid.

[0958] The product was confirmed by LCMS and H-NMR.

[0959] 1 H NMR (400MHz, CDCl3) δ: 8.29 (s, 1H), 7.72 (d, 2H, J = 8.4Hz), 6.79 (d, 2H, J = 8.4Hz), 5.44 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.49 (s, 3H).

[0960] Step 3

[0961] methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[0962] Methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[0963] Methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I153 (0.79 g, 2.2 mmol) was dissolved in THF (15 mL), and 2,4-dimethoxybenzylamine (0.6 g, 15.4 mmol) was added. The reaction system was stirred at 60°C for 1 hour. After the reaction, the reaction solution was added to cold water (50 mL), filtered to obtain a solid, washed with water, and dried to obtain methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate I154 (0.7 g, 71.4% yield) as a white solid.

[0964] The product was confirmed by LCMS and H-NMR.

[0965] 1 H NMR (400MHz, CDCl3) δ: 8.27 (d, 1H, J = 2.4Hz), 8.13 (t, 1H, J = 6.0Hz), 7.71 (dd, 1H, J = 8.4, 2.4Hz), 7.18 (d, 1H, J = 8.4Hz), 6.76 (d,1H,J=8.4Hz),6.44-6.49(m,2H),5.36(s,2H),4.28(d,1H,J=6.4Hz),3.96(s,3H),3.86(s,3H),3.82(s,3H),3.80(s,3H).

[0966] Step 4

[0967] methyl 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate

[0968] 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[0969] Methyl 5-((2,4-dimethoxyphenyl)amino)-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate I154 (0.67 g, 1.50 mmol) was dissolved in DCM / H₂O (25 / 5 mL). DDQ (1.37 g, 6.02 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 1 hour. After the reaction was complete, 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 give methyl 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylate I155 (290 mg, 65.3% yield) as a yellow solid.

[0970] The product was confirmed by LCMS and H-NMR.

[0971] 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).

[0972] Step 5

[0973] methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0974] Methyl 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[0975] 4-(Pyrrolidin-1-yl)butan-1-amine (189 mg, 1.33 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0 °C, CDI (191 mg, 1.33 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (5 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((6-methoxypyridin-3-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I155 (280 mg, 0.95 mmol) and potassium carbonate (262 mg, 1.90 mmol) were added, and the reaction system was stirred at room temperature for 8 hours. After the reaction is complete, water (20 mL) is added to the reaction solution, and the mixed solution is extracted with dichloromethane (10 mL x 3). The organic phase is washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1) to give a yellow solid product 3-((6-methoxypyridin-3-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I156 (230 mg, 52.3% yield).

[0976] The product was confirmed by LCMS and H-NMR.

[0977] 1 H NMR (400MHz, CDCl3) δ: 10.30 (br s, 1H), 8.28 (d, 1H, J = 2.0Hz), 8.01 (br s,1H),7.71(dd,1H,J=8.4,2.4Hz),6.76(d,1H,J=8.8Hz),5.37(s,2H),3.95(s,3H) ,3.85(s,3H),3.32(s,2H),2.51-2.60(m,6H),1.87-1.89(m,4H),1.66-1.68(m,4H).

[0978] Step 6

[0979] 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-

[0980] carboxamide

[0981] 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide

[0982] 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 sealed and reacted at 60°C for 72 hours. 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) to give 3-[(6-methoxypyridin-3-yl)methoxy]-5-({[4-(pyrrolidin-1-yl)butyl]carbamoyl}amino)-4,5-dihydro-1,2-thiazole-4-carboxamide T033 (23 mg, 10.8% yield) as a white solid.

[0983] The product was confirmed by LCMS, H-NMR and C-NMR.

[0984] 1 H NMR (400MHz, CD3OD) δ: 8.29 (d, 1H, J = 2.4Hz), 7.86 (dd, 1H, J = 8.4, 2.0Hz), 6.84 (d, 1H, J = 8.8Hz), 5.44 (s, 2H), 3.93(s,3H),3.26(t,2H,J=6.8Hz),2.69(s,4H),2.62(t,2H,J=7.2Hz),1.84-1.88(m,4H),1.59-1.62(m,4H).

[0985] 13 C NMR(100MHz,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.

[0986] Example 21: Synthesis of Compound T035

[0987] The synthetic route is as follows:

[0988] first step

[0989] 6-(bromomethyl)-2-methylbenzo[d]oxazole

[0990] 6-(Bromomethyl)-2-methylbenzo[d]oxazole

[0991] Dissolve (2-methyl-1,3-benzoxazol-6-yl)methanol (1 g, 6.1 mmol) in DCM (10 mL), cool to 0°C, add PBr3 (1.66 g, 6.1 mmol), and stir the reaction at room temperature for approximately half an hour. After completion of the reaction, concentrate under reduced pressure to obtain the crude product 6-(bromomethyl)-2-methylbenzo[d]oxazole I163 (1.1 g, crude) as a yellow solid.

[0992] The product was confirmed by LCMS.

[0993] Step 2

[0994] methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0995] Methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[0996] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (1 g, 4.42 mmol) and potassium carbonate (0.61 g, 4.42 mmol) were dissolved in DMF (20 mL). 6-(bromomethyl)-2-methylbenzo[d]oxazole I163 (1.05 g, 4.42 mmol) was added, and the reaction system was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction solution, and the solid was filtered and dried to give the crude product as a yellow solid, methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I164 (1 g, 59.2% yield).

[0997] The product was confirmed by LCMS and H-NMR.

[0998] 1 H NMR (400MHz, DMSO-d6) δ: 7.79 (s, 1H), 7.69 (s, 1H, J = 8.0Hz), 7.47 (s, 1H, J = 0.8Hz), 5.60 (s, 2H), 3.88 (s, 3H), 3.62 (s, 3H), 2.62 (s, 3H).

[0999] Step 3

[1000] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1001] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1002] Methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I164 (1 g, 2.61 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (4.37 g, 26.15 mmol) was added. The reaction system was stirred at 65°C for 1 hour. After completion of the reaction, the reaction solution was added to water (30 mL) and filtered to obtain a solid. After drying, a yellow solid product, methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate I165 (550 mg, 77% yield) was obtained.

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

[1004] 1 H NMR (400MHz, DMSO-d6) δ: 8.41 (t, 1H, J = 6.0Hz), 7.70 (s, 1H), 7.63 (d, 1H, J = 8.0Hz), 7.38-7.40 (m, 1H), 7.16 (d, 1H, J = 8.0Hz), 6.5 9(d,1H,J=2.4Hz),6.50(dd,1H,J=8.0,2.0Hz),5.43(s,2H),4.27(d,1H,J=6.0Hz),3.82(s,3H),3.73-3.74(m,6H),2.60(s,3H).

[1005] Step 4

[1006] methyl 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate

[1007] 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[1008] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate I165 (1 g, 2.13 mmol) was dissolved in DCM / H₂O (10 / 2 mL). DDQ (1.93 g, 8.52 mmol) was added portionwise at 0°C, and the mixture was stirred for 1 hour. After the reaction was complete, 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 afford methyl 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylate I166 (300 mg, 44.1% yield) as a yellow solid.

[1009] The product was confirmed by LCMS and H-NMR.

[1010] 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).

[1011] Step 5

[1012] methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1013] Methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1014] 4-(Pyrrolidin-1-yl)butan-1-amine (134 mg, 0.94 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (300 mg, 0.94 mmol) was added and the reaction was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-amino-3-((2-methylbenzo[d]oxazol-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I166 (300 mg, 0.94 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added and the reaction system was stirred at room temperature for 2 hours. After the reaction is complete, water (20 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (20 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a yellow solid product 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I167 (200 mg, 43.7% yield).

[1015] The product was confirmed by LCMS.

[1016] Step 6

[1017] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1018] 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1019] In a microwave tube, methyl 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I167 (200 mg, 0.41 mmol) was dissolved in NH3 / MeOH (5 mL, 9 mol / L), and the mixture was sealed and reacted at 60°C for 16 hours. The reaction solution 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 3-((2-methylbenzo[d]oxazol-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T035 (15 mg, 11.9% yield) as a white solid.

[1020] The product was confirmed by LCMS, H-NMR and C-NMR.

[1021] 1 H NMR(400MHz,CDCl3)δ:10.96(br s,1H),7.75(br s,1H),7.68(d,1H,J=8Hz),7.56(s,1H),7.40-7.42(m,2H),7.13(s,1H),5.57(s,2H) ,5.53(s,1H),3.34(s,2H),2.67-2.71(s,3H),2.57(s,3H),1.92(s,4H),1.71(s,4H).

[1022] 13 C NMR(100MHz, CDCl3)δ:169.62,165.97,164.74,161.73,154.15,151.07,141.83,132.67,124.74,119.51,110.55,70.40,55.81,53.88,40.91 28.00,26.43,23.36,14.59,1.02.

[1023] Example 22: Synthesis of Compound T036

[1024] The synthetic route is as follows:

[1025] first step

[1026] 1-(bromomethyl)-4-ethoxybenzene

[1027] 1-(Bromomethyl)-4-ethoxybenzene

[1028] (4-Ethoxyphenyl)methanol (500 mg, 3.29 mmol) was dissolved in DCM (15 mL), the temperature was lowered to 0°C, and PBr3 (296 mg, 1.10 mmol) was added. The reaction system was stirred at 10°C for approximately 1 hour. After the reaction was complete, the mixture was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product 1-(bromomethyl)-4-ethoxybenzene I168 (600 mg, 84.9% yield) as a yellow oily liquid.

[1029] The product was confirmed by LCMS and H-NMR.

[1030] 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).

[1031] Step 2

[1032] methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1033] Methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1034] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-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-ethoxybenzene I168 (544 mg, 2.53 mmol) was added, and the reaction system was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction solution, and the solid was filtered. The filter cake was washed with water and then dried to give the crude product, methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I169 (610 mg, 77.9% yield), as a pale white solid.

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

[1036] 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).

[1037] Step 3

[1038] methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate

[1039] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate

[1040] Methyl 3-((4-ethoxybenzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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, the reaction solution was added to water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA = 10 / 1-5 / 1-3 / 1) to obtain methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate I170 (550 mg, 89.1% yield) as a pale white solid.

[1041] The product was confirmed by LCMS and H-NMR.

[1042] 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).

[1043] Step 4

[1044] methyl 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate

[1045] 5-Amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[1046] Methyl 5-((2,4-dimethoxybenzyl)amino)-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate I170 (550 mg, 1.20 mmol) was dissolved in DCM / H2O (11 / 2.2 mL). DDQ (817 mg, 3.60 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 1 hour. After the reaction was complete, water (40 mL) was added to the reaction solution, the solid was filtered off, and the filtrate was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE / EA = 20 / 1-10 / 1-5 / 1-1 / 1) to obtain methyl 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylate I171 (290 mg, 78.4% yield) as a yellow solid.

[1047] The product was confirmed by LCMS and H-NMR.

[1048] 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).

[1049] Step 5

[1050] methyl 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1051] Methyl 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1052] 4-(Pyrrolidin-1-yl)butan-1-amine (129 mg, 0.91 mmol) was dissolved in anhydrous THF (5 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (147 mg, 0.91 mmol) was added and the reaction was stirred at room temperature for 1 hour. DMSO (5 mL) was added and most of the THF was removed under reduced pressure. 5-amino-3-((4-ethoxybenzyl)oxy)isothiazole-4-carboxylic acid methyl ester I171 (200 mg, 0.65 mmol) and potassium carbonate (179 mg, 1.30 mmol) were added and the reaction system was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added to the reaction solution, and the solid was filtered to obtain the solid. The filter cake was washed with water and dried to obtain the crude product as a pale white solid product 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I172 (180 mg, 58.2% yield).

[1053] The product was confirmed by LCMS and H-NMR.

[1054] 1 H NMR(400MHz,CDCl3)δ:10.22(br s,1H),8.18(br s,1H),7.41(d,2H,J=8.8Hz),6.91(d,1H,J=8.8Hz),5.39(s,2H),4.06(q,2H,J=7.2Hz),3.96(s,3H ),3.33(d,2H,J=5.2Hz),2.52-2.64(m,6H),1.89-1.91(m,4H),1.68(s,4H),1.44(t,3H,J=7.2Hz).

[1055] Step 6

[1056] 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1057] 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1058] 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 sealed and reacted at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O (25%) = 100 / 10 / 1) to give 3-((4-ethoxybenzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T036 (30 mg, 31.0% yield) as a white solid.

[1059] The product was confirmed by LCMS, H-NMR and C-NMR.

[1060] 1 H NMR (400MHz, CDCl3) δ: 10.91 (s, 1H), 7.82 (s, 1H), 7.38 (d, 2H, J = 8.8Hz), 7.18 (s, 1H), 6.92 (d, 2H, J = 8.4Hz), 5.60 (s, 1H), 5.39(s,2H),4.06(q,2H,J=7.2Hz),3.33(s,2H),2.51-2.58(m,6H),1.86(s,4H),1.67-1.68(m,4H),1.44(t,3H,J=7.2Hz).

[1061] 13 C NMR(100MHz, 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.

[1062] Example 23: Synthesis of Compound T042

[1063] The synthetic route is as follows:

[1064] first step

[1065] 2,3-dihydrobenzofuran-6-carboxylic acid

[1066] 2,3-Dihydrobenzofuran-6-carboxylic acid

[1067] 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 a hydrogen atmosphere (20 psi) for 16 hours. After the reaction was complete, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford the crude product 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 91.4% yield) as a white solid.

[1068] The product was identified by LCMS and H-NMR.

[1069] 1 H NMR (400MHz, DMSO-d6) δ7.46 (dd, 1H, J = 7.6, 1.6Hz), 7.32 (d, 1H, J = 7.6Hz), 7.23 (d, 1H, J = 1.2Hz), 4.57 (t, 2H, J = 8.8Hz), 3.23 (t, 2H, J = 8.8Hz).

[1070] Step 2

[1071] (2,3-dihydrobenzofuran-6-yl)methanol

[1072] (2,3-Dihydrobenzofuran-6-yl)methanol

[1073] Under N₂ protection, 2,3-dihydrobenzofuran-6-carboxylic acid I193 (3.7 g, 22.54 mmol) was dissolved in anhydrous THF (50 mL). BH₃.Me₂S (10 M, 5.63 mL, 56.3 mmol) was added in an ice-water bath. The mixture was stirred at 60°C for 16 hours. The reaction mixture was poured into methanol (100 mL) and concentrated under reduced pressure to afford the crude product (2,3-dihydrobenzofuran-6-yl)methanol I194 (3.3 g, 97.49% yield) as a colorless liquid.

[1074] The product was confirmed by LCMS and used directly in the next reaction.

[1075] Step 3

[1076] 6-(bromomethyl)-2,3-dihydrobenzofuran

[1077] 6-(Bromomethyl)-2,3-dihydrobenzofuran

[1078] (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 system was stirred at room temperature for approximately 1 hour. After the reaction was complete, the mixture was added with cold saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (4 g, 85.3% yield) as a white product.

[1079] The product was confirmed by LCMS.

[1080] Step 4

[1081] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1082] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1083] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (1.0 g, 4.21 mmol) and potassium carbonate (1.17 g, 8.43 mmol) were dissolved in DMF (10 mL), and 6-(bromomethyl)-2,3-dihydrobenzofuran I195 (0.99 g, 4.64 mmol) was added. The reaction system was stirred at room temperature for 4 hours. Water (50 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 (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by flash column chromatography (PE / EA = 10 / 1) to obtain methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I196 (1.2 g, 77.1% yield) as a white solid.

[1084] The product was confirmed by LCMS and H-NMR.

[1085] 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).

[1086] Step 5

[1087] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1088] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1089] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 60°C for 4 hours. After the reaction, 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, washed sequentially with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I197 (1.3 g, 75.1% yield) as a white solid.

[1090] The product was confirmed by LCMS and H-NMR.

[1091] 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).

[1092] Step 6

[1093] methyl 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylate

[1094] 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[1095] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I197 (1.64 g, 3.59 mmol) was dissolved in DCM / H2O (15 / 3 mL). DDQ (1.22 g, 5.39 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 20 minutes. After the reaction is complete, water (30 mL) is added to the reaction solution, and the mixture is extracted with DCM (30 mL x 2). The combined organic phases are washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by chromatography column (PE / EA = 10 / 1-3 / 1) to give a yellow solid product, 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I198 (0.4 g, 36.4% yield).

[1096] The product was confirmed by LCMS.

[1097] Step 7

[1098] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1099] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[1100] 4-(Pyrrolidin-1-yl)butan-1-amine (390 mg, 2.74 mmol) was dissolved in anhydrous THF (10 mL). Under N2 protection, the temperature was lowered to 0 °C, CDI (445 mg, 2.74 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (10 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((2,3-dihydrobenzofuran-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I198 (0.6 g, 1.96 mmol) and potassium carbonate (541 mg, 3.92 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (40 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (20 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product is purified by preparative thin layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give a yellow solid product 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I199 (0.6 g, 64.6% yield).

[1101] The product was confirmed by LCMS.

[1102] Step 8

[1103] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1104] 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1105] In a microwave tube, methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I199 (400 mg, 0.84 mmol) was dissolved in NH3 / MeOH (20 mL, 9 mol / L), and the mixture was sealed and stirred at 60°C for 16 hours. 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 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.

[1106] The product was confirmed by LCMS, H-NMR and C-NMR.

[1107] 1 H NMR (400MHz, CDCl3) δ: 11.67 (br s, 1H), 11.10 (s, 1H), 7.37 (s, 1H), 7.21 (d, 1H, J = 6.4Hz), 6.92 (d, 1H, J = 7.6Hz), 6.87 (s, 1H), 6.14 (br s,1H),5.38(s,2H),4.61(t,2H,J=8.8Hz),3.79(s,2H),3.37-3.38(m,2H),3.23(t,2H,J=8.8 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).

[1108] 13 C NMR(100MHz,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.

[1109] Example 24: Synthesis of Compound T044

[1110] The synthetic route is as follows:

[1111] first step

[1112] 5-(bromomethyl)-2,3-dihydrobenzofuran

[1113] 5-(Bromomethyl)-2,3-dihydrobenzofuran

[1114] 5-(Hydroxymethyl)-2,3-dihydrobenzofuran (1 g, 6.66 mmol) was dissolved in DCM (10 mL), cooled to 0°C, and PBr3 (2.7 g, 9.99 mmol) was added. The reaction system was stirred at room temperature for approximately 1 hour. After complete reaction, the mixture was added with cold saturated aqueous sodium bicarbonate solution (20 mL x 2). After separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 5-(bromomethyl)-2,3-dihydrobenzofuran I203 as a white solid (1.2 g, 84.6% yield).

[1115] The product was confirmed by LCMS.

[1116] Step 2

[1117] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1118] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1119] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (0.5 g, 2.11 mmol) and potassium carbonate (0.58 g, 4.21 mmol) were dissolved in DMF (5 mL), and 5-(bromomethyl)-2,3-dihydrobenzofuran I203 (494 mg, 2.32 mmol) was added. The reaction system was stirred at room temperature for 16 hours. 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 (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by flash column chromatography (PE / EA = 10 / 1) to obtain methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I204 (0.5 g, 64.2% yield) as a white solid.

[1120] The product was confirmed by LCMS and H-NMR.

[1121] 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).

[1122] Step 3

[1123] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1124] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate

[1125] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 60°C for 4 hours. After the reaction, 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 with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I205 (0.19 g, 76.9% yield) as a white solid.

[1126] The product was confirmed by LCMS.

[1127] Step 4

[1128] methyl 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylate

[1129] 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[1130] Methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I205 (683 mg, 1.50 mmol) was dissolved in DCM / H2O (5 / 1 mL). DDQ (509 mg, 2.24 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for half an hour. After the reaction was complete, the mixture was filtered, and the filtrate was added to water (10 mL). The mixture was 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 methyl 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylate I206 (0.1 g, 21.8% yield) as a yellow solid.

[1131] The product was confirmed by LCMS.

[1132] Step 5

[1133] methyl 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1134] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester

[1135] 4-(Pyrrolidin-1-yl)butan-1-amine (65.mg, 0.46mmol) was dissolved in anhydrous THF (2mL), and the temperature was lowered to 0°C under N2 protection. CDI (74mg, 0.46mmol) was added, and the reaction was stirred for 30 minutes, and then stirred at room temperature for 1 hour. DMSO (2mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((2,3-dihydrobenzofuran-5-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I206 (0.1g, 0.33mmol) and potassium carbonate (90mg, 0.65mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete, water (20 mL) is added to the reaction solution, the mixed solution is extracted with ethyl acetate (20 mL x 3), the organic phase is washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product as a yellow oily liquid product 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I207 (0.1 g, 64.6% yield).

[1136] The product was confirmed by LCMS.

[1137] Step 6

[1138] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1139] 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1140] In a microwave oven, 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 give a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH = 10 / 1, 1% NH3.H2O) to give 3-((2,3-dihydrobenzofuran-5-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T044 (18 mg, 7.44% yield) as a white solid.

[1141] The product was confirmed by LCMS, H-NMR and C-NMR.

[1142] 1 H NMR (400MHz, CDCl3): 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=8.4Hz),3.59(s,1H),3.37(s,2H),4 .59-4.63(m,2H),3.26-3.37(m,2H),3.06-3.26(m,2H),2.93-2.99(m,4H), 2.86-2.92(m,2H),2.03-2.35(m,4H),1.86-2.00(m,2H),1.65-1.86(m,2H).

[1143] 13 C NMR(100MHz, CDCl3)δ:169.34,165.76,162.15,160.53,154.25,129.15,127.89,127.60,125.84,1 09.34,97.49,71.50,71.42,70.63,55.46,53.85,39.80,39.74,29.58,29.49,27.40,25.02,23.37

[1144] Example 25: Synthesis of Compound T045

[1145] The synthetic route is as follows:

[1146] first step

[1147] 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine

[1148] 3-Bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine

[1149] 5-Bromopyridin-3-ol (1.5 g, 8.62 mmol) was dissolved in DMF (15.0 mL), and 1-(2-chloroethyl)pyrrolidine hydrochloride (1.76 g, 10.35 mmol) and sodium hydroxide (1.38 g, 34.48 mmol) were added. The reaction system was heated to 70°C and stirred for 2 hours. The reaction solution was poured into water (60 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Purification by flash column chromatography afforded 3-bromo-5-(2-(pyrrolidin-1-yl)ethoxy)pyridine I208 (1.6 g, 68.5% yield) as a yellow oily liquid.

[1150] The product was confirmed by LCMS.

[1151] Step 2

[1152] 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine

[1153] 5-(2-(Pyrrolidin-1-yl)ethoxy)pyridin-3-amine

[1154] 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 the reaction was complete, the insoluble material was filtered off through celite. The filtrate was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Purification by flash column chromatography (DCM / MeOH = 120 / 1-40 / 1, 0.1% NH3·H2O) afforded 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine I209 as a yellow solid (0.6 g, 78.5% yield).

[1155] The product was confirmed by LCMS.

[1156] Step 3

[1157] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-

[1158] carboxylate

[1159] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylic acid

[1160] ester

[1161] 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), and LiHMDS (1 M, 4.50 mL) and 5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-amine I209 (464 mg, 2.24 mmol) were added at room temperature, and the reaction was stirred at 30°C for 5 hours. After the reaction is complete, the mixture is poured into water (50 mL), extracted with ethyl acetate, and the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which is purified by flash column chromatography (DCM / MeOH=150 / 1-120 / 1) to give a yellow oily liquid product, 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxylic acid methyl ester I210 (0.27 g, 23.3% yield).

[1162] The product was confirmed by LCMS.

[1163] Step 4

[1164] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-

[1165] carboxamide

[1166] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((5-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)amino)isothiazole-4-carboxamide

[1167] 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 sealed and stirred at 65°C for 16 hours. 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 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) as a white solid.

[1168] The product was confirmed by LCMS, H-NMR and C-NMR.

[1169] 1 H NMR(400MHz, DMSO-d6)δ:11.17(s,1H),8.08-8.13(m,2H),7.69(s,1H),7.57-7.59(d,2H,J=8.0Hz),7.2 8-7.29(m,1H),6.85(s,1H),5.51(s,2H).4.19(t,2H,J=5.6Hz),2.85(s,2H),2.57(m,4H),1.70(s,4H).

[1170] 13 C NMR(100MHz, CDCl3+CD3OD)δ:172.32,166.01,162.87,162.80,160.35,160.26,155.27,137.15,132.64,132.0 4,123.56,115.87,115.65,115.58,111.02,110.91,110.84,96.47,66.41,58.01,54.62,54.35,29.62,23.24.

[1171] Example 26: Synthesis of Compound T046

[1172] The synthetic route is as follows:

[1173] first step

[1174] tert-butyl 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1175] tert-Butyl 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1176] 4-(2-Hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (3 g, 13.0 mmol) was dissolved in THF (30 mL), and 4-nitro-1H-pyrazole (1.6 g, 14.3 mmol), DIAD (4 g, 19.5 mmol) and PPh3 (5.1 g, 19.5 mmol) were added at room temperature, followed by stirring for 2 hours. After the reaction was complete, the mixture was added to water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product as a yellow solid product 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylic acid tert-butyl ester I211 (5 g, crude product) which was used directly in the next reaction.

[1177] The product was confirmed by LCMS.

[1178] Step 2

[1179] tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1180] tert-Butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate

[1181] Crude tert-butyl 4-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate I211 (5 g) and Pd / C (0.5 g) were dissolved in anhydrous methanol (MeOH) (100 mL) and stirred at room temperature under 50 psi of H2 for 2 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to afford the crude product tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate I212 (2.5 g, 55% yield) as a red solid.

[1182] The product was identified by LCMS and H-NMR.

[1183] 1 H NMR (400MHz, CDCl3) δ: 7.17 (s, 1H), 7.10 (s, 1H), 4.14 (t, 2H, J = 6.4Hz), 3.43 (t, 4H, J = 4.8Hz), 2.79 (t, 1H, J = 6.4Hz), 2.42 (s, 4H), 1.47 (s, 9H).

[1184] Step 3

[1185] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-

[1186] 4-yl)amino)isothiazole-4-carboxylate

[1187] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino

[1188] 4-[4-(2-Yl)isothiazole-4-carboxylic acid methyl ester

[1189] Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylate I178 (300 mg, 0.68 mmol) and tert-butyl 4-(2-(4-amino-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate 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, followed by stirring and reacting for about 1 hour. After the reaction was complete, 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 give a crude product, which was purified by high performance preparative chromatography to give 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 (10 mg, 2.2% yield) as a white solid.

[1190] The product was identified by LCMS and H-NMR.

[1191] 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).

[1192] Step 4

[1193] tert-butyl 4-(2-(4-((3-((4-bromo-2,6-difluorobenzyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-

[1194] yl)ethyl)piperazine-1-carboxylate

[1195] 4-(2-(4-((3-((4-bromo-2,6-difluorophenyl)oxy)-4-carbamoylisothiazol-5-yl)amino)-1H-pyrazol-1-yl)ethyl)piperazine-

[1196] tert-Butyl 1-carboxylate

[1197] In a microwave tube, 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), and the mixture was sealed and stirred at 70°C for 48 hours. 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 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.

[1198] The product was confirmed by LCMS and H-NMR.

[1199] 1 H NMR (400MHz, CDCl3) δ: 10.09 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 7.19 (d, 2H, J = 6.8Hz), 6.83 (s, 1H), 5. 54(s,2H),5.34(s,1H),4.53(s,2H),3.62(s,4H),2.54-2.66(m,4H),1.63-1.68(m,2H),1.47(s,9H).

[1200] Example 27: Synthesis of Compound T049

[1201] The synthetic route is as follows:

[1202] first step

[1203] N,3-dimethylbenzamide

[1204] N, 3-dimethylbenzamide

[1205] N,3-Dimethylbenzoic acid (5 g, 36.72 mmol) was dissolved in anhydrous DMF (50 mL). Methylamine hydrochloric acid (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 and stirred for 3 hours. After the reaction was complete, the mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography (PE / EA = 3 / 1 to 1 / 1) to obtain N,3-dimethylbenzamide I218 (4.8 g, 87.6% yield) as a yellow oily liquid.

[1206] The product was confirmed by LCMS and H-NMR.

[1207] 1 H NMR (400MHz, CDCl3) δ: 7.61 (s, 1H), 7.49-7.57 (m, 1H), 7.31-7.34 (m, 2H), 6.23 (s, 1H), 3.03 (d, 3H, J = 4.4Hz), 2.41 (s, 3H).

[1208] Step 2

[1209] 3-(bromomethyl)-N-methylbenzamide

[1210] 3-(Bromomethyl)-N-methylbenzamide

[1211] N,3-Dimethylbenzamide I218 (4 g, 26.81 mmol) was dissolved in CCl4 (80 mL), and AIBN (440 mg, 2.68 mmol) and NBS (5.73 g, 32.17 mmol) were added at room temperature. The mixture was heated to 80°C in an oil bath and stirred under reflux for 16 hours. After the reaction was complete, the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by flash column chromatography (PE / EA = 10 / 1-5 / 1-1 / 1) to obtain 3-(bromomethyl)-N-methylbenzamide I219 (4.6 g, crude) as a brown oily liquid.

[1212] Step 3

[1213] methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1214] Methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1215] 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), and 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, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The product was purified by flash column chromatography (PE / EA = 5 / 1-3 / 1-1 / 1-1 / 2) to obtain methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I220 (2.4 g, 74.06% yield) as a white solid.

[1216] The product was confirmed by LCMS and H-NMR.

[1217] 1 H NMR (400MHz, CDCl3) δ: 7.93 (s, 1H), 7.72 (d, 1H, J = 7.6Hz), 7.60 (d, 1H, J = 8.0Hz), 7.47 (t, 1H,J=8.0Hz),6.23(s,1H),5.54(s,2H),4.00(s,3H),3.50(s,3H),3.05(d,3H,J=5.2Hz).

[1218] Step 4

[1219] methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate

[1220] Methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate

[1221] Methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(methylsulfonyl)isothiazole-4-carboxylate 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 system was stirred at 65°C for 1 hour. After the reaction, the reaction solution was added to water (100 mL), and the mixture was filtered to obtain a filter cake, which was washed with water and dried to obtain a white solid product, methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate I221 (2.2 g, 89.7% yield).

[1222] The product was confirmed by LCMS and H-NMR.

[1223] 1 H NMR (400MHz, CDCl3) δ: 8.13 (t, 1H, J = 5.6Hz), 7.91 (s, 1H), 7.71 (d, 1H, J = 7.6Hz), 7.59 (d, 1H, J = 8.0Hz), 7.44 (t, 1H, J = 7.6Hz), 7.18 ( d,1H,J=8.4Hz),6.39-6.50(m,2H),6.21(s,1H),5.46(s,2H),4.29(d,2H,J=6.0Hz),3.87(s,6H),3.82(s,3H),3.04(d,2H,J=4.8Hz).

[1224] Step 5

[1225] methyl 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate

[1226] 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester

[1227] Methyl 5-((2,4-dimethylbenzyl)amino)-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate I221 (2 g, 4.24 mmol) was dissolved in DCM / H2O (150 / 30 mL). DDQ (3.85 g, 16.97 mmol) was added portionwise at 0°C. The reaction system was stirred at room temperature for 5 minutes. After the reaction was complete, neutral alumina was added to the mixture, and the solution was concentrated under reduced pressure. The mixture was purified by column chromatography (neutral alumina, PE / EA = 100 / 1-50-1-20 / 1) to give methyl 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylate I222 (1 g, 73.37% yield) as a pale yellow solid.

[1228] The product was confirmed by LCMS.

[1229] Step 6

[1230] methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1231] Methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1232] 4-(Pyrrolidin-1-yl)butan-1-amine (177 mg, 1.24 mmol) was dissolved in anhydrous THF (4 mL). Under N2 protection, the temperature was lowered to 0°C. CDI (179 mg, 1.24 mmol) was added, and the reaction was stirred for 30 minutes. Then, the reaction was stirred at room temperature for 1 hour. DMSO (4 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-((3-(methylcarbamoyl)benzyl)oxy)isothiazole-4-carboxylic acid methyl ester I222 (400 mg, 1.24 mmol) and potassium carbonate (344 mg, 2.49 mmol) were added, and the reaction system was stirred at room temperature for 1 hour. After the reaction is complete, water (20 mL) is added to the reaction solution, and the mixed solution is extracted with ethyl acetate (10 mL x 3). The organic phase is washed with water (30 mL) and saturated brine (30 mL) in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylic acid methyl ester I223, which is directly used in the next reaction.

[1233] The product was confirmed by LCMS and H-NMR.

[1234] 1 H NMR(400MHz,CDCl3)δ:10.23(br s,1H),8.10(br s,1H),7.94(s,1H),7.70(d,1H,J=5.6Hz),7.59(d,1H,J=7.6Hz),7.44(t,1H,J=7.6Hz),6.30(s,1H),5.47(s,2H),3.9 0(s,3H),3.31(s,2H),3.04(d,3H,J=4.8Hz),2.59(s,4H),2.52(t,2H,J=6.0Hz),1.86-1.88(m,4H),1.66-1.68(m,4H).

[1235] Step 7

[1236] 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1237] 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1238] In a microwave tube, methyl 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I223 (150 mg, 0.31 mmol) was dissolved in NH3 / MeOH (15 mL, 9 mol / L). The mixture was sealed and stirred at 65°C for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by high-performance preparative chromatography to obtain 3-((3-(methylcarbamoyl)benzyl)oxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T049 (25.7 mg, 17.7% yield) as a white solid.

[1239] The product was confirmed by LCMS, H-NMR and C-NMR.

[1240] 1 H NMR(400MHz, CDCl3)δ:10.92(br s,1H),7.88(s,2H),7.76(d,1H,J=7.6Hz),7.59(d,1H,J=7.2Hz),7.48(t,1H,J=8.0Hz),7.12(s,2H),6.22(s,1H),5.52( s,2H),5.48(s,1H),3.33(s,3H),3.05(d,3H,J=4.8Hz),2.59(s,4H),2.48-2.56(m,2H),1.88(s,4H),1.71-1.69(m,4H).

[1241] 13 C NMR(100MHz, CDCl3+CD3OD)δ:173.17,172.60,169.79,165.76,158.43,140.24,138.82,1 35.08,132.85,131.04,130.83,73.83,59.91,57.88,43.82,31.52,30.45,29.70,27.07.

[1242] Example 28: Synthesis of Compound T050

[1243] The synthetic route is as follows:

[1244] first step

[1245] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-

[1246] carboxamide

[1247] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxamide

[1248] 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 (50 mg, 0.078 mmol) was dissolved in HCl / MeOH (5 mL, 8 mol / L) at room temperature and stirred for 2 h. After the reaction was complete, the mixed solution was directly concentrated under reduced pressure, water was added to the residue, the pH was adjusted to 9 with saturated sodium carbonate, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1) to give 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((1-(2-(piperazin-1-yl)ethyl)-1H-pyrazol-4-yl)amino)isothiazole-4-carboxamide T050 (18.8 mg, 44.5% yield) as a white solid product.

[1249] The product was confirmed by LCMS, H-NMR and C-NMR.

[1250] 1 H NMR(400MHz, CDCl3)δ:10.04(s,1H),7.60(s,1H),7.49(s,1H),7.18-7.25(m,2H),6.82(s,1H),5.54 (s,2H),5.32(s,1H),4.24(t,2H,J=6.0Hz),2.92-2.95(m,4H),2.80-2.83(m,2H),2.37-2.50(m,2H).

[1251] 13 C NMR(100MHz, CDCl3)δ:176.72,166.01,162.96,162.91,162.89,160.43, 160.35,133.93,132.55,123.55,123.42,123.30,123.05,122.46,115.91 ,115.88,115.82,115.69,115.64,115.61,115.54,111.36,111.16,94.2 8,58.18,57.68,57.64,57.61,54.27,54.20,54.17,50.26,46.00,45.93.

[1252] Example 29: Synthesis of Compound T051

[1253] The synthetic route is as follows:

[1254] first step

[1255] ethyl 5,6-dichloronicotinate

[1256] 5,6-Dichloronicotinate ethyl ester

[1257] 5,6-Dichloronicotinic acid (15 g, 78 mmol) and thionyl chloride (27.6 g, 234 mmol) were dissolved in ethanol (150 mL), and the reaction system was stirred at 60°C for 1.0 hour. The reaction solution was concentrated under reduced pressure, and the residue was poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 5,6-dichloronicotinic acid ethyl ester I224 (15 g, 87% yield) as a white solid.

[1258] The product was confirmed by LCMS and H-NMR

[1259] 1 H NMR (400MHz, CDCl3) δ8.89(d,J=2.0Hz,1H),8.37(d,J=1.6Hz,1H),4.44(dd,J=21.6,7.0Hz,2H),1.43(t,J=7.2Hz,3H).

[1260] Step 2

[1261] ethyl 5-chloro-6-cyanonicotinate:

[1262] 5-Chloro-6-cyanonicotinoic acid ethyl ester

[1263] Ethyl 5,6-dichloronicotinate I224 (8 g, 36 mmol), zinc cyanide (3.16 mg, 27 mmol), and tetrakis(triphenylphosphine)palladium (4.15 g, 3.6 mmol) were dissolved in DMF (80 mL). The reaction system was stirred at 100°C for 16 hours. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 50:1 to 30:1) to obtain ethyl 5-chloro-6-cyanonicotinate I225 (3 g, 38.7% yield) as a white solid.

[1264] The product was confirmed by LCMS and H-NMR

[1265] 1 H NMR (400MHz, CDCl3) δ9.17(d,J=1.6Hz,1H),8.46(d,J=1.6Hz,1H),4.49(q,J=7.1Hz,2H),1.46(t,J=7.2Hz,3H).

[1266] Step 3

[1267] ethyl 6-(aminomethyl)-5-chloronicotinate:

[1268] 6-(Aminomethyl)-5-chloronicotinate ethyl ester

[1269] Ethyl 5-chloro-6-cyanonicotinate I225 (8.8 g, 41.78 mmol) was dissolved in acetic acid (100 mL), and Raney nickel (2.45 g, 41.78 mmol) was added. The reaction system was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, ethyl 6-(aminomethyl)-5-chloronicotinate I226 (4.40 g, 58.4% yield), as a green solid.

[1270] The product was confirmed by LCMS and H-NMR.

[1271] 1 H NMR (400MHz, D2O) δ8.74(s,1H),8.13(s,1H),4.27(s,3H),4.13(s,2H),1.10(s,3H).

[1272] Step 4

[1273] ethyl 5-chloro-6-(formamidomethyl)nicotinate:

[1274] 5-Chloro-6-(formamidomethyl)nicotinate ethyl ester

[1275] Ethyl 6-(aminomethyl)-5-chloronicotinate I226 (8.8 g, 41.00 mmol) was dissolved in acetic anhydride (20 mL) and formic acid (100 mL). The reaction system was stirred at 100°C for 16 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product ethyl 5-chloro-6-(formamidomethyl)nicotinate I227 (6 g, 60.3% yield) as a white solid.

[1276] The product was confirmed by LCMS.

[1277] Step 5

[1278] ethyl 8-chloroimidazo[1,5-a]pyridine-6-carboxylate

[1279] Ethyl 8-chloroimidazo[1,5-a]pyridine-6-carboxylate

[1280] Ethyl 5-chloro-6-(formamidomethyl)nicotinate I227 (6 g, 24.73 mmol) was dissolved in toluene (50 mL) and phosphorus oxychloride (15.17 g, 98.90 mmol) was added. The reaction system was stirred at 100°C for 16 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 1:1) to obtain ethyl 8-chloroimidazo[1,5-a]pyridine-6-carboxylate I228 (2.5 g, 45.0% yield) as a yellow solid.

[1281] The product was confirmed by LCMS and H-NMR.

[1282] 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.69 (s, 1H), 7.54 (s, 1H), 7.22 (d, J = 0.4Hz, 1H), 4.34 (d, J = 7.2Hz, 2H), 1.34 (t, J = 7.2Hz, 3H).

[1283] Step 6

[1284] (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol

[1285] (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol

[1286] Ethyl 8-chloroimidazo[1,5-a]pyridine-6-carboxylate I228 (2 g, 8.90 mmol) was dissolved in THF (20 mL). DIBAL-H (7.2 mL, 35.61 mmol) was added dropwise at 0°C. The reaction system was stirred at room temperature for 2.0 hours. The reaction solution was quenched with water (15 mL), filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10:1 to 2:1) to obtain (8-chloroimidazo[1,5-a]pyridin-6-yl)methanol I229 (360 mg, 22.14% yield) as a yellow solid.

[1287] The product was confirmed by LCMS and H-NMR.

[1288] 1 H NMR (400MHz, DMSO-d6) δ8.49(s,1H),8.27(s,1H),7.42(s,1H),6.93(s,1H),5.42(t,J=5.6Hz,1H),4.42-4.44(m,2H).

[1289] Step 7

[1290] 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine

[1291] 6-(Bromomethyl)-8-chloroimidazo[1,5-a]pyridine

[1292] (8-Chloromidazo[1,5-a]pyridin-6-yl)methanol I229 (270 mg, 1.48 mmol) was dissolved in DCM (20 mL) and PBr3 (400 mg, 1.48 mmol) was added. The reaction system was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to afford the crude product 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine I230 (330 mg, 90.9% yield) as a yellow solid.

[1293] The product was confirmed by LCMS.

[1294] Step 8

[1295] methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1296] Methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate

[1297] Methyl 3-hydroxy-5-(methylsulfonyl)isothiazole-4-carboxylate I009 (319 mg, 1.34 mmol) was dissolved in DMF (5 mL), and 6-(bromomethyl)-8-chloroimidazo[1,5-a]pyridine I230 (330 mg, 1.34 mmol) and potassium carbonate (557 mg, 4.03 mmol) were added. The reaction system was stirred at room temperature for 2 hours. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography (PE / EA=1:1) to give a yellow solid product, methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I231 (120 mg, 22.2% yield).

[1298] The product was confirmed by LCMS and H-NMR.

[1299] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.57 (s, 1H), 8.53 (s, 1H), 7.49 (s, 1H), 7.11 (s, 1H), 5.44 (s, 1H), 3.89 (s, 1H), 3.62 (s, 1H).

[1300] Step 9

[1301] methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-

[1302] carboxylate

[1303] 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylic acid methyl ester

[1304] Methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(methylsulfonyl)isothiazole-4-carboxylate I231 (120 mg, 0.30 mmol) was dissolved in THF (10 mL), and 2,4-dimethoxybenzylamine (50 mg, 0.30 mmol) was added. The reaction system was stirred at 60°C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic 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 HPLC to obtain methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I232 (60 mg, 41.1% yield) as a yellow solid.

[1305] The product was confirmed by LCMS and H-NMR.

[1306] 1 H NMR (400MHz, DMSO-d6) δ8.55(s,1H),8.42(s,1H),7.46(s,1H),7.17(d,J=7.7Hz,1H),7.05(s,1H) ,6.60(s,1H),6.51(d,J=7.7Hz,1H),5.27(s,2H),4.29(d,J=5.2Hz,2H),3.84(s,3H),3.76(s,6H).

[1307] Step 10

[1308] methyl 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylate

[1309] 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester

[1310] Methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-((2,4-dimethoxybenzyl)amino)isothiazole-4-carboxylate I232 (50 mg, 0.10 mmol) was dissolved in DCM (5 mL) and water (1 mL), and DDQ (93 mg, 0.41 mmol) was added portionwise at 0°C. The reaction system was stirred at 0°C for 0.5 h. The reaction solution was poured into water (10 mL), extracted with DCM (10 mL x 3), and the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative thin layer chromatography (PE / EA=1 / 1) to give a yellow solid product, 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I233 (13.5 mg, 38.9% yield).

[1311] The product was confirmed by LCMS and HNMR.

[1312] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.56 (s, 1H), 8.43 (s, 1H), 7.47 (s, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 5.27 (s, 2H), 3.73 (s, 3H).

[1313] Step 11

[1314] methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1315] Methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate

[1316] 4-(Pyrrolidin-1-yl)butan-1-amine (12 mg, 83 μmol) was dissolved in anhydrous THF (2 mL). Under N2 protection, CDI (13 mg, 83 μmol) was added and the reaction was stirred at room temperature for 2.0 hours. DMSO (2 mL) was added, and the THF was removed under reduced pressure. 5-amino-3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)isothiazole-4-carboxylic acid methyl ester I233 (20 mg, 59 μmol) and potassium carbonate (16 mg, 118 μmol) were added, and the reaction system was stirred at room temperature for 2.0 hours. The reaction solution was poured into water (8 mL), and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative thin layer chromatography (DCM / MeOH=10 / 1) to give a yellow solid product, methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I234 (15 mg, 50.11% yield).

[1317] The product was confirmed by LCMS and H-NMR.

[1318] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.44 (s, 1H), 8.36 (s, 1H), 7.48 (s, 1H), 7.06 (s, 1H), 5.33 (s, 2H), 3.9 1(s,3H),3.32-3.34(m,2H),2.73(m,4H),2.66-2.68(m,2H),1.87-1.88(m,4H),1.60-1.62(m,4H).

[1319] Step 12

[1320] 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1321] 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide

[1322] Methyl 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxylate I234 (14 mg, 28 μmol) was dissolved in NH3 / MeOH (1 mL, 10 mol / L). The mixture was stirred and reacted at 65°C for 16 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by preparative thin-layer chromatography (DCM / MeOH / NH3.H2O=10 / 1 / 0.1%) to give a yellow solid product, 3-((8-chloroimidazo[1,5-a]pyridin-6-yl)methoxy)-5-(3-(4-(pyrrolidin-1-yl)butyl)ureido)isothiazole-4-carboxamide T051 (1.2 mg, 8.83% yield).

[1323] The product was confirmed by LCMS and HNMR.

[1324] 1 H NMR (400MHz, CD3OD): δ (ppm) 8.46 (s, 1H), 8.43 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H) ),5.45(s,2H),3.24(s,2H),2.05-2.07(s,2H),1.96(s,4H),1.76(s,4H)1.62-1.66(m,4H).

[1325] Example 30: Synthesis of Compound T052

[1326] The synthetic route is as follows:

[1327] first step

[1328] N,N-dimethyl-3-(4-nitro-2H-1,2,3-triazol-2-yl)propan-1-amine

[1329] N, N-dimethyl-3-(4-nitro-2H-1,2,3-triazol-2-yl)propan-1-amine

[1330] (3-Chloropropyl)dimethylamine hydrochloride (3.05 g, 19.29 mmol) was dissolved in acetonitrile (20.0 mL), and 4-nitro-2H-1,2,3-triazole (2 g, 17.53 mmol) and potassium carbonate (2.67 g, 19.29 mmol) were added. The reaction system was heated to 80°C and stirred for 16 hours. After the reaction was complete, the reaction solution was poured into water (50 mL) and extracted with ethyl acetate (20 mL x 3). 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 product was purified by flash column chromatography (DCM / MeOH = 120 / 1 to 50 / 1) to obtain N,N-dimethyl-3-(4-nitro-2H-1,2,3-triazol-2-yl)propan-1-amine I235 (1.6 g, 45.8% yield) as a yellow oily liquid.

[1331] The product was confirmed by LCMS and HNMR.

[1332] 1 H NMR (400MHz, DMSO-d6): δ (ppm) 8.69 (s, 1H), 4.55-4.59 (m, 2H), 2.20-2.23 (m, 2H), 2.11 (s, 6H), 2.02-2.07 (m, 2H).

[1333] Step 2

[1334] 2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-amine

[1335] 2-(3-(Dimethylamino)propyl)-2H-1,2,3-triazol-4-amine

[1336] N,N-dimethyl-3-(4-nitro-2H-1,2,3-triazol-2-yl)propan-1-amine I235 (1.6 g, 8.03 mmol) and Pd / C (146 mg) were dissolved in anhydrous methanol (MeOH) (20 mL) and stirred at 30°C under a hydrogen balloon for 16 hours. After the reaction was complete, the mixture was filtered through celite and washed with methanol. The filtrate was concentrated under reduced pressure to afford the crude product 2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-amine I236 (1.3 g, 95.6% yield) as a yellow oily liquid.

[1337] The product was identified by LCMS.

[1338] Step 3

[1339] methyl 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxylate

[1340] Methyl 3-[(4-bromo-2,6-difluorophenyl)methoxy]-5-methylsulfonyl-1,2-thiazole-4-carboxylate I178 (1 g, 2.26 mmol) and 2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-amine I236 (421 mg, 2.49 mmol) were dissolved in anhydrous THF (20 mL), and LiHMDS (1 M, 5.00 mL) was added at room temperature, followed by stirring at 30 ° C for about 2 hours. After complete reaction, water (30 mL) and ethyl acetate (20 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 give a crude product, which was purified by high performance preparative chromatography to give a yellow oily liquid product, 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxylic acid methyl ester I237 (0.2 g, 16.7% yield).

[1341] The product was identified by LCMS.

[1342] Step 4

[1343] 3-((4-bromo-2,6-difluorobenzyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxamide

[1344] 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxamide

[1345] In a microwave tube, methyl 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxylate I237 (0.3 g, 0.56 mmol) was dissolved in NH3 / MeOH (10 mL, 9 mol / L), and the mixture was sealed and stirred at 65°C for 16 hours. 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 3-((4-bromo-2,6-difluorophenyl)oxy)-5-((2-(3-(dimethylamino)propyl)-2H-1,2,3-triazol-4-yl)amino)isothiazole-4-carboxamide T052 (25.6 mg, 8.78% yield) as a white solid.

[1346] The product was confirmed by LCMS, H-NMR and C-NMR.

[1347] 1 H NMR (400MHz, CD3OD) δ: 7.48 (s, 1H), 7.33-7.35 (d, 2H, J = 8.0Hz), 5.56 (s, 2H), 4.43-4.46 (m, 2H), 2.42-2.46 (m, 2H), 2.30 (s, 6H), 2.16-2.20 (m, 2H).

[1348] 13 C NMR(100MHz, CDCl3)δ:171.30,166.09,162.99,162.91,161.82,160.45,160.37,145.69,123.39,120.71,115. 90,115.87,115.82,115.68,115.63,115.61,111.43,95.48,57.75,57.72,57.68,56.38,53.15,45.40,27.35.

[1349] Example 31: Synthesis of Compound T053

[1350] The synthetic route is as follows:

[1351] first step

[1352] methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(2-(1-methylpiperidin-4-yl)ethyl)ureido)isothiazole-4-carboxylate

[1353] Methyl 3-((2,3-dihydrobenzofuran-6-yl)methoxy)-5-(3-(2-(1-methylpiperidin-4-yl)ethyl)ureido)isothiazole-4-carboxylate

[1354] 2-(1-Methylpiperidin-4-yl)ethan-1-amine (150 mg, 1.05 mmol) was dissolved in anhydrous THF (10 mL). Under N2 protection, the temperature was lowered to 0 °C, CDI (170 mg, 1.05 mmol) was added, and the reaction was stirred at room temperature for 1 hour. DMSO (10 mL) was added, and most of the THF was removed under reduced pressure. 5-amino-3-[(2,3-dihydro-1-benzofuran-6-yl)methoxy]-1,2-thiazole-4-carboxylic acid methyl ester I198 (230 mg, 0.75 mmol) and potassium carbonate (208 mg, 1.50 mmol) were added, and the reaction system was stirred at room temperature for 16 hours. After the reaction is complete...

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or deuterated compound thereof, wherein the compound has the following structure: in, Ring A is a 5-7 membered heteroaromatic ring; B ring is 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 combined with C6-C 10 Aromatic ring, C5-C8 aliphatic ring, 5-10 membered heterocyclic ring fusion; X1 is O or S; Y is -N(C0-C 10 Alkyl)(C0-C 10 alkyl) or -O(C0-C 10 alkyl); L1 is selected from the group consisting of 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-, and -Cy-; -Cy- is selected from the group consisting of a substituted or unsubstituted cycloalkylene group, a substituted or unsubstituted arylene group, and a substituted or unsubstituted heterocyclylene group; L2 is a single bond or an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted by a group 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; wherein a and b are independently selected from integers of 0-10, R L201 and R L202 Independently selected from: H, C1-C 10 Alkyl, 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-C6 cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl; wherein, R L203 and R L204 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; L3 is an alkylene group, wherein one or more methylene units in the alkylene group are optionally and independently substituted by a group 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; wherein c and d are independently selected from integers of 0-10, R L301 and R L302 Independently selected from: 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 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, heterocyclyl, heterocyclylalkyl; wherein, R L303 and R L304 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; Each R3 to R5 is independently selected from: 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 is optionally substituted with a group selected from the following: halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; R1 is one or more independent substituents on the B ring, each R1 is independently selected from: 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 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 Fang -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), -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 the C1-C 10 Alkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group is optionally substituted by a group selected from the group consisting of 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 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; 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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 wherein the alkyl, cycloalkyl, heterocyclic group is optionally substituted by a group selected from the group consisting of 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 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; m is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valence permits); R0 is selected from: H, C1-C 10 Alkyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -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, the E ring is 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 combined with C6-C 10 Aromatic ring, C5-C8 aliphatic ring, 4-10 membered heterocyclic ring fusion; R2 is selected from: 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 , 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), -SO2(CH2) j (C3-C 10 Cycloalkyl), -S(CH2) j (C3-C 10 Cycloalkyl), -O(CH2) j (C3-C 10 Cycloalkyl), wherein j is an integer from 0 to 5; wherein the C1-C 10 Alkyl, C6-C 10 Aryl, 4-10 membered heterocyclic group is optionally substituted by a group selected from the group consisting of 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, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, 5, if valence permits); 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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 Silane, wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted by a group selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; 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 heterocyclyl, substituted or unsubstituted heterocyclylalkyl, C1-C 10 Silane, wherein the alkyl, cycloalkyl, heterocyclyl is optionally substituted by a group selected from the group consisting of halogen, cyano, nitro, azido, -OR', -C(O)R', -C(O)OR', -OC(O)R', -NR'C(O)OR", -NR'S02R", -SO2NR'R", -NR'C(O)R", -C(O)NR'R", -NR'R", -SR', -SOR', -SO2R', -SO3H, C1-C 10 Alkyl, C1-C 10 Halogenated alkyl, C1-C 10 Silane, C3-C 10 Cycloalkyl, phenyl, 4-10 membered heterocyclic group; R' and R" 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, and substituted or unsubstituted heterocyclylalkyl.

2. The compound according to claim 1, wherein Ring A is in particular Preferably, The section has the following structure: in particular 3. The compound according to claim 1 or 2, wherein Ring B is a benzene ring, a benzoaliphatic ring, or a heterocyclic ring; Preferably, Ring B is selected from: More preferably, Partially selected from the following structures:

4. The compound according to any one of claims 1 to 3, wherein Each R1 is independently selected from: C1-C6 alkyl, halogen, 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; Preferably, R 101 and R 102 Independently selected from: 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 hydroxy-substituted alkyl (e.g., ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 amino substituted 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 heterocyclic group (e.g. )、 C1-C 10 Silyl-substituted alkyl groups (e.g. ), C1-C 10 Silane groups (such as )； More preferably, each R1 is independently selected from: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, -OH, 5. The compound according to any one of claims 1 to 4, characterized in that R0 is Ring E is a 4-10 membered heterocycle, especially a 4-8 membered saturated heterocycle; Preferably, the E ring is selected from: More preferably, Part of 6. The compound according to any one of claims 1 to 5, characterized in that R2 is selected from: H, =O, C1-C6 alkyl, C1-C6 haloalkyl, 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 heterocyclic group), -(CH2) j (C3-C 10 cycloalkyl), wherein j is an integer from 0 to 5; Preferably, R 201 and R 202 Independently selected from: 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 hydroxy-substituted alkyl (e.g., ), C1-C6 alkoxy substituted alkyl (e.g. ), C1-C6 amino-substituted 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 heterocyclic group (e.g. )、 More preferably, R2 is selected from the group consisting of: H, methyl, ethyl, n-propyl, isopropyl, -CF3, -CHF2, -CH2F, F, Cl, Br, I, cyano, nitro, azido, hydroxy, methoxy, ethoxy, Further preferably, R0 is selected from:

7. The compound according to any one of claims 1 to 4, characterized in that R0 is -NR 001 R 002 , where R 001 and R 002 independently selected from the group consisting of: 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: R0 is selected from: H, cyano, -O(CO-C 10 Alkyl), -O(C1-C 10 Silane), -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 by a group selected from the group consisting of halogen, cyano, hydroxy, amino, C1-C6 alkoxy, C1-C6 alkylamino, C3-C6 cycloalkyl; Preferably, R0 is selected from: H, cyano, -OH, -COOH、 8. The compound according to any one of claims 1 to 7, wherein 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 group; More preferably, -Cy- is selected from:

9. The compound according to any one of claims 1 to 8, 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 by a group selected from the group consisting of: -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 by a group consisting of: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, L2 is C2-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the group consisting of: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-; More preferably, L2 is selected from: a single bond, 10. The compound according to any one of claims 1 to 9, characterized in that L3 is C1-C6 alkylene, wherein one or more methylene units in the alkylene are optionally and independently substituted by a group selected from the following: -NH-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, wherein one or more H atoms in the alkylene are optionally and independently substituted by a group selected from the following: H, C1-C6 alkyl, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C4-C 10 cycloalkylalkyl; Preferably, L3 is methylene.

11. The compound according to claim 1, wherein The compound is selected from:

12. The compound according to claim 1, wherein The stereoisomers are selected from:

13. The compound according to claim 1, wherein L1 is -C(O)NR3- or a single bond, Part of Wherein, R1 contains at least one of the following groups: 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl), wherein t is an integer from 0 to 5; preferably, The section has the following structure: Among them, R 1b 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl); more preferably, R 1b Selected from: 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 heterocyclic group), -(CH2) t (C3-C6 cycloalkyl), wherein t is an integer from 0 to 5; R 1c Selected from: 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 heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl); R 1a 、R 1d 、R 1e Selected from: H, C1-C6 alkyl (such as methyl, ethyl, n-propyl, isopropyl), halogen (such as F, Cl, Br, I), 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 、-SR 101 、-S(O)2R 101 、-SO3H、-(CH2) t (phenyl), -(CH2) t (4-10 membered heterocyclic group), -(CH2) t (C3-C 10 cycloalkyl); or, L1 is -C(O)NR3-, and ring B is a monocyclic heterocycle, for example Part of L1 is -C(O)NR3-, and ring B is a fused bicyclic ring, for example Part of L1 is -Cy-.

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

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

16. The use according to claim 15, characterized in that The disease is a tumor, in particular a malignant tumor, preferably selected from the group consisting of breast cancer, lung cancer, adenocarcinoma, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, myeloma, unrelated myeloid metaplasia, mesothelioma, myelodysplastic syndrome, and hematological malignancies; or, The disease is an eye disease, preferably selected from: diabetic retinopathy (including simple (background) diabetic retinopathy, proliferative diabetic retinopathy and diabetic macular edema); age-related macular degeneration (including neovascular (wet) AMD (exudative / exudative), dry AMD, geographic atrophy); pathological choroidal neovascularization (i.e., high myopia, trauma, sickle cell disease; ocular histoplasmosis, angioid streaks, traumatic choroidal rupture, optic nerve drusen, and certain retinal dystrophies); pathological retinal neovascularization (i.e., sickle cell retinopathy, Eales' disease, ocular ischemic syndrome, carotid cavernous fistula, familial exudative vitreoretinopathy, hyperviscosity syndrome, idiopathic occlusive arteritis, avian retinochoroidopathy, retinal vasculitis, sarcoidosis, or toxoplasmosis); uveitis; retinal vein occlusion (central or branch); ocular trauma; Surgical edema; surgical neovascularization; cystoid macular edema; ocular ischemia; retinopathy of prematurity; Koch's disease; sickle cell retinopathy and / or neovascular glaucoma.