Compound for EGFR protein degradation and use thereof

Abstract

The present invention relates to a compound for EGFR protein degradation and a use thereof. Specifically, the compound of the present invention has a structure represented by formula III, wherein the definition of each group and substituent is as described in the description. Also disclosed in the invention are a preparation method for the compound and a use of same in the prevention and / or treatment of EGFR-related diseases.

Description

Compounds for EGFR protein degradation and uses thereof Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to compounds for EGFR protein degradation and uses thereof. Background Art

[0002] The HER family of receptor tyrosine kinases is a mediator of cell growth, differentiation, and survival. This receptor family includes four different members, namely the epidermal growth factor receptor (EGFR, ErbB1 or HER1), HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4). After ligand binding, the receptor forms homodimers or heterodimers, and subsequent activation of endogenous tyrosine kinase activity leads to receptor autophosphorylation and activation of downstream signaling molecules. It has been shown that the regulation of EGFR activation caused by overexpression or mutation is involved in many types of human cancers including colorectal cancer, pancreatic cancer, glioma, head and neck cancer, and lung cancer, especially non-small cell lung cancer (NSCLC). Over the years, a variety of EGFR-targeted agents have been developed, and three generations of drugs are already in clinical use.

[0003] In actual clinical practice, patients typically develop EGFR T790M resistance mutations 8-12 months after using first- or second-generation EGFR inhibitors, resulting in the drug losing its therapeutic effect. Although third-generation EGFR inhibitors, such as osimertinib and ametinib, have been shown to effectively overcome resistance to EGFR T790M mutations, resistance mutations such as EGFR C797S can still emerge after a period of use, leading to disease progression.

[0004] The problem of mutation resistance that frequently occurs during the treatment with EGFR small molecule tyrosine kinase inhibitors has become a difficult problem that needs to be solved clinically. Although some EGFR allosteric inhibitor compounds, such as EAI045, have been reported to overcome C797S resistance, the clinical effect is limited. In recent years, some patents (WO2019149922, WO2021127561) have reported that a series of PROTAC-type compounds can overcome the C797S resistance problem by degrading EGFR protein, which has become a new research direction.

[0005] In summary, although some progress has been made in EGFR allosteric inhibitors and EGFR degraders, this field still needs to find more clinically valuable EGFR protein-regulating drugs for the treatment of diseases currently caused by EGFR dysregulation, especially in the field of EGFR-positive non-small cell lung cancer. Summary of the Invention

[0006] An object of the present invention is to provide a compound represented by formula I.

[0007] Another object of the present invention is to provide the use of the compound represented by Formula I in preventing and / or treating EGFR-related diseases.

[0008] In the first aspect of the present invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof,

[0009] in,

[0010] X3 is selected from none, NH, NR;

[0011] X2 is selected from NR, O, S;

[0012] Each R is independently selected from C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0013] X1 is selected from CH, N;

[0014] X4 is selected from CH, N;

[0015] Ring B Selected from the following groups: substituted or unsubstituted 6-7 membered heterocyclyl, substituted or unsubstituted 7-9 membered heterospirocyclyl; the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the following groups: H, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 hydroxyalkyl;

[0016] Ring A is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 6-10 membered heteroaryl; the substitution means that 0-1 hydrogen atoms on the group are replaced by R6, and m hydrogen atoms are replaced by R7; m is 0, 1, or 2;

[0017] in,

[0018] R6 is selected from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogenated C 1-6 Alkyl, -P(O)RaRb, -C(O)R, -C(O)NHR, -C(O)NRaRb, -OC(O)-OR, -OC(O)NHR, -OC(O)NRaRb, -S(O)2R, -NR-S(O)2R, -NR-C(O)-OR, -NH-C(O)-OR, C1-4 Alkyl-substituted or unsubstituted 4-7 membered heterocyclyl-O-;

[0019] Ra and Rb are each independently C 1-6 Alkyl, C 3-6 Cycloalkyl, or Ra and Rb together with the heteroatom to which they are attached form a 5-7 membered heterocyclic ring;

[0020] R7 is selected from the group consisting of H, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 hydroxyalkyl;

[0021] R1 is selected from halogen;

[0022] R2 is selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 2-6 membered heteroalkyl; wherein the heteroalkyl contains at least one heteroatom selected from the group consisting of O, N and S, wherein the substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of cyano, nitro, hydroxyl, amino and halogen;

[0023] R3 is selected from halogen;

[0024] Each R4 is independently H, halogen;

[0025] Each R5 is independently H, halogen, C 1-6 Alkyl; or two R5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl;

[0026] R8 is selected from: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0027] In another preferred embodiment, R6 is located at the adjacent position to the linking site.

[0028] In another preferred embodiment, ring A is selected from the following group:

[0029] Wherein, R6, R7, and m are as described in the first aspect of the present invention.

[0030] In another preferred embodiment, ring B is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl.

[0031] In another preferred embodiment, ring B Substituted by a substituent selected from the group consisting of H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0032] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -P(O)RaRb, -C(O)NHR, -C(O)NRaRb, -OC(O)NHR, -OC(O)NRaRb, -S(O)2R, -NR-S(O)2R, -NR-C(O)-OR, -NH-C(O)-OR;

[0033] Ra and Rb are each independently C 1-4 Alkyl, C 3-6 Cycloalkyl, or Ra and Rb together with the heteroatom to which they are attached form a 5-membered heterocyclic ring.

[0034] In another preferred embodiment, the compound has the structure shown in Formula II-1:

[0035] in,

[0036] X1 is selected from CH, N;

[0037] X2 is selected from NR;

[0038] R is selected from C 1-3 Alkyl, halogenated C 1-3 Alkyl (preferably CF3);

[0039] X3 is selected from none, NH;

[0040] R1 is selected from halogen;

[0041] R2 is selected from: H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 2-4 membered heteroalkyl; wherein the heteroalkyl contains at least one heteroatom selected from the group consisting of O, N and S, wherein the substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of cyano, nitro, hydroxyl, amino and halogen;

[0042] R3 is selected from halogen;

[0043] Each R4 is independently H, halogen;

[0044] Each R5 is independently H, halogen, C 1-3 Alkyl; or two R5 together with the carbon atom to which they are attached form a C 3-4 cycloalkyl;

[0045] R6 is selected from the group consisting of:

[0046] R7 is selected from the group consisting of H, C 3-6 Cycloalkyl, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0047] R8 is selected from the following group: C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0048] m is 0, 1, or 2.

[0049] In another preferred embodiment, R4 and R5 are not halogen at the same time.

[0050] In another preferred embodiment, R4 is F, and R5 is H.

[0051] In another preferred embodiment, R4 is H, and R5 is F.

[0052] In another preferred embodiment, R2 is ethyl.

[0053] In another preferred embodiment, R1 is Cl or Br.

[0054] In another preferred embodiment, R7 is H, Br, cyclopropyl, methoxy, ethyl, methyl, F, Cl, or isopropyl.

[0055] The second aspect of the present invention provides a compound, which is a compound of formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof,

[0056] in,

[0057] X3 is selected from the group consisting of none, NH, NR, and O;

[0058] X2 is selected from the group consisting of NR, O, and S;

[0059] Each R is independently selected from the group consisting of: C 1-6 Alkyl, C 6-10 aryl;

[0060] X1 is selected from the group consisting of CH, N;

[0061] X 11Selected from the group consisting of: CH, N;

[0062] X4 is selected from the group consisting of N, CR';

[0063] X5 is selected from the group consisting of CH, N, and C;

[0064] X 51 Selected from the group consisting of C-(OH), N, C;

[0065] Ring B Selected from the following groups: substituted or unsubstituted 6-7 membered heteromonocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-9 membered heterobridged cycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-10 membered heterospirocycloalkylene containing 1-3 heteroatoms selected from N, O or S; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0066] Ring C Selected from the following groups: substituted or unsubstituted 6-7 membered heteromonocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-9 membered heterospirocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 4-10 membered heterobridged cycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 5-7 membered heteroarylene containing 1-3 heteroatoms selected from N, O or S; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0067] Ring A is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; the substitution means that one hydrogen on the group is replaced by R6, and m hydrogens are replaced by R7;

[0068] R6 is selected from the following group: C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, -P(O)RaRb, -C(O)Ra, -C(O)NRaRb, -OC(O)NRaRb, -S(O)2Ra, -NRa-S(O)2Rb, -NRa-C(O)-ORa,

[0069] Ra and Rb are each independently selected from the group consisting of H, C 1-6 alkyl;

[0070] R7 is selected from the group consisting of H, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl;

[0071] R1 is halogen;

[0072] R2 is selected from the group consisting of H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 alkyl;

[0073] R3 is halogen;

[0074] R4 is selected from the group consisting of H, halogen;

[0075] R5 is selected from the group consisting of H, halogen;

[0076] R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 Alkyl; or R8 and R' and the atoms to which they are attached together form a 5-6 membered heterocyclic group containing 1 O;

[0077] L is selected from the following group:

[0078] Each R' is independently selected from the group consisting of H, C 1-6 alkyl;

[0079] m is selected from the following group: 0, 1, 2;

[0080] n is selected from the following group: 0, 1, 2;

[0081] n1 is selected from the following group: 0, 1, 2;

[0082] m1 is selected from the following group: 0, 1, 2;

[0083] m2 is selected from the following group: 0, 1, 2.

[0084] In another preferred embodiment, X3 is selected from the following group: none, NH, NR, O.

[0085] In another preferred embodiment, X3 is NH.

[0086] In another preferred embodiment, X2 is selected from the following group: NR, O, S.

[0087] In another preferred embodiment, X2 is -N(C 1-6 alkyl)-.

[0088] In another preferred embodiment, X1 is selected from the following group: CH, N.

[0089] In another preferred embodiment, X1 is N.

[0090] In another preferred embodiment, X 11 Selected from the group consisting of CH, N.

[0091] In another preferred embodiment, X 11 is N.

[0092] In another preferred embodiment, X4 is selected from the following group: N, CR'.

[0093] In another preferred embodiment, X4 is CH.

[0094] In another preferred embodiment, X5 is selected from the following group: CH, N, C.

[0095] In another preferred embodiment, X5 is selected from the following group: CH, C.

[0096] In another preferred embodiment, X 51 Selected from the group consisting of C-(OH), N, C.

[0097] In another preferred embodiment, X 51 is N.

[0098] In another preferred embodiment, ring A is

[0099] wherein R6, R7, and m are as described above.

[0100] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, -P(O)RaRb, -C(O)NRaRb, -OC(O)NRaRb, -S(O)2Ra, -NRa-S(O)2Rb, -NRa-C(O)-ORa,

[0101] In another preferred embodiment, R6 is selected from the following group: -P(O)RaRb, -C(O)NRaRb.

[0102] In another preferred embodiment, Ra and Rb are independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl.

[0103] In another preferred embodiment, Ra is selected from the following group: H, C 1-6 alkyl.

[0104] In another preferred embodiment, Rb is C 1-6 alkyl.

[0105] In another preferred embodiment, R2 is selected from the following group: H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 alkyl.

[0106] In another preferred embodiment, R2 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0107] In another preferred embodiment, R2 is C 1-6 alkyl.

[0108] In another preferred embodiment, R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 or R8 and R' and the atoms to which they are attached together form a 5-6 membered heterocyclic group containing 1 O.

[0109] In another preferred embodiment, R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0110] In another preferred embodiment, R8 is C 1-6 alkyl.

[0111] In another preferred embodiment, ring B is a substituted or unsubstituted group selected from the following group: Wherein, the substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl.

[0112] In another preferred embodiment, ring C Select from the following groups:

[0113] In another preferred embodiment, L is selected from the following group:

[0114] In another preferred embodiment, the compound is selected from the following group: a compound of formula II', a compound of formula III', a compound of formula IV':

[0115] in,

[0116] X1 is selected from the group consisting of CH, N;

[0117] X2 is NR;

[0118] R is C 1-3 alkyl;

[0119] X3 is selected from the group consisting of: none, NH;

[0120] R1 is halogen;

[0121] R2 is selected from the group consisting of H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 alkyl;

[0122] R3 is halogen;

[0123] R 41 Selected from the group consisting of: H, halogen;

[0124] R 42 Selected from the group consisting of: H, halogen;

[0125] R4 is selected from the group consisting of H, halogen;

[0126] R5 is selected from the group consisting of H, halogen;

[0127] R6 is selected from the group consisting of:

[0128] Ra and Rb are each independently selected from the group consisting of H, C 1-6 alkyl;

[0129] R7 is selected from the group consisting of H, C 3-6 Cycloalkyl, halogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0130] R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0131] m is selected from the following group: 0, 1, 2.

[0132] In the third aspect of the present invention, there is provided a compound of formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof,

[0133] Where,

[0134] X1 and X5 are each independently selected from CH, N, C;

[0135] X2 is selected from NR, O and S;

[0136] X3 is selected from the group consisting of no (bond), NH, NR and O;

[0137] X4, X6 and X7 are each independently selected from the group consisting of CR or N;

[0138] Each R is independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, C 6-10 Aryl or C 6- 10 aryloxy;

[0139] L is m and n are each independently 0, 1, 2, 3 or 4;

[0140] R7, R8 and the P to which they are connected together form Cy1, which is selected from the following group: a saturated or partially unsaturated 4-7 membered ring containing P=O, wherein the ring, in addition to P, further comprises 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and the ring is optionally substituted with one or more substituents R a Replace; or

[0141] R7 and R8 are each independently selected from the following group: C1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 hydroxyalkyl;

[0142] R a Selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3 to 8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -CN, -OR b 、-COR b 、-COOR b 、CONR b R c 、-NR b R c 、-NR b COR c or -NR b COOR c , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally replaced by R d replace;

[0143] R b 、R c and R d Each independently selected from the group consisting of hydrogen, hydroxyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 3-8 Cycloalkyl;

[0144] R1 is selected from halogen;

[0145] R2 is selected from H, halogenated C 1-6 Alkyl, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 Alkyl, halogen, -(CH2) p -C 1-4 Alkoxy, -(CH2) p -Halogenated C 1-4 Alkoxy, -(CH2) p -CN、C 1-6 Alkyl-substituted or unsubstituted 5-6 membered heteroaryl and 2-6 membered heteroalkyl containing 1-3 heteroatoms selected from N, O or S; wherein the heteroalkyl or heterocycloalkyl contains one or more heteroatoms independently selected from the group consisting of O, N and S; p is 0, 1, 2, or 3;

[0146] R3 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 hydroxyalkyl;

[0147] R4 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 hydroxyalkyl;

[0148] R5 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxy, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 hydroxyalkyl;

[0149] Alternatively, R4 and R5 form a C3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from O, N or S;

[0150] R6 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 Alkyl, or C 1-6 Hydroxyalkyl; or, X4 is CR, and R of X4 is connected to R6 to form a saturated or partially saturated 5-6 membered heterocyclic group containing 1 O;

[0151] Ring B Selected from the following groups: substituted or unsubstituted 6-7 membered heterocyclyl, substituted or unsubstituted 7-12 membered heterospirocyclyl, substituted or unsubstituted 7-12 membered heterobridged cyclyl; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following groups: H, D, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, wherein q is 1, 2, 3, 4, or 5 (such as compounds TB-081, TB-056, etc.);

[0152] Ring C is selected from the group consisting of: a substituted or unsubstituted 6-7 membered heterocyclylene, a substituted or unsubstituted 5-6 membered heteroarylene, or a substituted or unsubstituted 7-12 membered heterospirocyclylene; wherein the substitution refers to the replacement of one or more hydrogen atoms on the group by a substituent selected from the group consisting of: H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5;

[0153] The heterocyclylene, heteroarylene, heterospirocyclylene and heterobridged cyclylene groups each independently contain 1 to 3 heteroatoms selected from N, S and O.

[0154] In another preferred embodiment, R is selected from the following group: C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, C 6-10 Aryl or C 6-10 Aryloxy.

[0155] In another preferred embodiment, R a Selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, -CN, -OR b 、-COR b 、-COOR b 、CONR b R c 、-NR b R c 、-NR b COR c or -NR b COOR c , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally replaced by R d replace;

[0156] R b 、R c and R d Each independently selected from the group consisting of hydrogen, hydroxyl, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl.

[0157] In another preferred embodiment, L is m and n are each independently 0, 1, or 2.

[0158] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0159] In another preferred embodiment, R3 is selected from the following group: H or halogen.

[0160] In another preferred embodiment, R4 is selected from the following group: H or halogen.

[0161] In another preferred embodiment, R5 is selected from the following group: H or halogen.

[0162] In another preferred embodiment, ring B is selected from the group consisting of a substituted or unsubstituted 6-7 membered heterocyclylene group, or a substituted or unsubstituted 7-10 membered heterospirocyclylene group; preferably, ring B is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5.

[0163] In another preferred embodiment, ring C is a substituted or unsubstituted group selected from the group consisting of a 6-7 membered heterocyclylene group, a 5-6 membered heteroarylene group, or a 7-10 membered heterospirocyclylene group; preferably, ring C is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5; R a 、R b and R are as described in the third aspect of the present invention.

[0164] In another preferred embodiment, the compound has a structure shown in Formula 2:

[0165] Where,

[0166] X2, X3, X4, X5, X6, X7, L, Cy1, ring C, R1, R2, R3, R4, R5, and R6 are as defined in the third aspect of the present invention.

[0167] In another preferred embodiment, the compound has a structure shown in Formula 2:

[0168] Where,

[0169] R', R" are each independently selected from the group consisting of D, halogen, oxo (=O), cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 hydroxyalkyl;

[0170] Or any two R' or two R" are connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5;

[0171] Alternatively, two R' or two R" attached to the same carbon atom may form a 3-6 membered saturated carbocyclic ring together with the attached carbon atom;

[0172] m and n are each independently selected from the following group: 0, 1, 2, 3;

[0173] X2, X3, X4, X5, X6, X7, L, Cy1, ring C, R1, R2, R3, R4, R5, and R6 are as defined in the third aspect of the present invention.

[0174] In another preferred embodiment, Select from the following groups:

[0175] In another preferred embodiment, X1 is N.

[0176] In another preferred embodiment, X5 is CH.

[0177] In another preferred embodiment, the compound has a structure shown in Formula 3:

[0178] Where,

[0179] X1, X3, X5, L, Cy1, ring C, R1, R2, R3, R4, R5, R6 and R are as defined in the third aspect of the present invention.

[0180] In another preferred embodiment, the compound has a structure shown in Formula 4:

[0181] Where,

[0182] X3, X5, L, Ring C, R1, R2, R3, R4, R5, R6 and R are as defined in the third aspect of the present invention.

[0183] In another preferred embodiment, ring C is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5; R a 、R b and R are as described in the third aspect of the present invention.

[0184] In another preferred embodiment, X2 is selected from NR, O and S; R is selected from the following group: CH3, phenyl, isopropyl, cyclopropyl.

[0185] In another preferred embodiment, R4 and R5 are each independently selected from the following group: H.

[0186] In another preferred embodiment, L is selected from the following group: ethylene,

[0187] In another preferred embodiment, X4 is selected from CH.

[0188] In another preferred embodiment, R2 is selected from ethyl.

[0189] In another preferred embodiment, R6 is selected from methyl.

[0190] In another preferred embodiment, R1 is selected from Cl and Br.

[0191] In another preferred embodiment, X3 is selected from NH.

[0192] In another preferred embodiment, X6 is selected from CR; R is selected from methoxy, cyclopropyl, and cyclopropyloxy.

[0193] In another preferred embodiment, X7 is selected from CH.

[0194] In another preferred embodiment, R3 is selected from H and F.

[0195] In a fourth aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, wherein the compound is selected from the group consisting of:

[0196] In the fifth aspect of the present invention, a pharmaceutical composition is provided, comprising (a) a therapeutically effective amount of the compound described in the first / second / third / fourth aspect of the present invention as an active ingredient, and (b) a pharmaceutically acceptable carrier.

[0197] In another preferred embodiment, component (a) accounts for 0.001-99.99 wt% of the total weight of the preparation; preferably 0.01-99.9 wt%; more preferably 0.05-90 wt%.

[0198] In another preferred embodiment, the pharmaceutical composition or preparation is in the form of an injection, tablet, capsule, pill, suspension or emulsion.

[0199] In another preferred embodiment, the pharmaceutical composition is in the form of an injection, tablet, capsule, pill, suspension or emulsion; preferably an injection.

[0200] In a sixth aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0201] (a1) first active ingredient: a therapeutically effective amount of the compound of the first / second / third / fourth aspect of the present invention;

[0202] (a2) a second active ingredient selected from the group consisting of gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panitumumab, pertuzumab, zalutumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tanespiramycin, aspiramycin, IPI-504, and NVP-AUY922; and

[0203] (b) a pharmaceutically acceptable carrier.

[0204] In the seventh aspect of the present invention, there is provided a use of the compound of the first / second / third / fourth aspect of the present invention, for use selected from the group consisting of:

[0205] 1) Preparation of drugs for regulating abnormal EGFR kinase activity;

[0206] 2) preparing drugs for preventing and / or treating diseases associated with abnormal EGFR kinase activity or mutation (preferably, diseases associated with EGFR drug-resistant mutations); and / or

[0207] 3) Preparation of drugs for degrading EGFR protein.

[0208] In another preferred embodiment, the abnormal EGFR kinase activity refers to EGFR kinase positive.

[0209] In another preferred embodiment, the abnormal EGFR kinase activity refers to overexpression of EGFR kinase.

[0210] In another preferred embodiment, the EGFR drug-resistant mutation is selected from the following group: EGFR T790M, EGFR C797S, DEL19, L858R, DEL19 / T790M, DEL10 / T790M / C797S, L858R / T790M / C797S.

[0211] In another preferred embodiment, the disease associated with abnormal EGFR kinase activity or mutation is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.

[0212] In another preferred embodiment, the cancer is selected from the following group: lung cancer (including lung adenocarcinoma, non-small cell lung cancer), breast cancer, prostate cancer, colorectal cancer, liver cancer, pancreatic cancer, ovarian cancer, leukemia, neuroblastoma, gastric cancer, kidney cancer, esophageal cancer, uterine cancer, glioma, head and neck cancer; preferably non-small cell lung cancer.

[0213] In another preferred embodiment, the EGFR-related disease is non-small cell lung cancer with an EGFR mutation selected from the group consisting of T790M / L858R, T790M / L858R / C797S, L858R, and L858R / C797S.

[0214] In an eighth aspect of the present invention, a method for preventing and / or treating diseases associated with EGFR drug-resistant mutations is provided, comprising the steps of:

[0215] 1) determining the EGFR kinase-activating mutation status of the subject in need;

[0216] 2) When the subject's EGFR activating mutation status satisfies treatment conditions, administering the compound of the first / second / third / fourth aspect of the present invention to the subject in need.

[0217] In another preferred embodiment, the “determining the patient's EGFR activating mutation status” is determined by the cobas EGFR mutation assay v2.

[0218] In another preferred embodiment, the EGFR drug-resistant mutation-related disease is non-small cell lung cancer.

[0219] In the ninth aspect of the present invention, a method for preventing and / or treating diseases associated with abnormal EGFR kinase activity or mutation is provided, comprising administering a therapeutically effective amount of the compound described in the first / second / third / fourth aspect of the present invention or the pharmaceutical composition described in the fifth or sixth aspect of the present invention to a subject in need.

[0220] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0221] In another preferred embodiment, the method is in vitro.

[0222] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. DETAILED DESCRIPTION

[0223] After extensive and in-depth research, the inventors unexpectedly developed a compound with excellent EGFR degradation properties. This compound has the structure shown in Formula I and exhibits excellent inhibitory and / or therapeutic effects against EGFR-related diseases (particularly diseases associated with EGFR resistance mutations), as well as excellent pharmacokinetic properties. Based on this, the inventors completed the present invention.

[0224] the term

[0225] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0226] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0227] "Alkyl (alone or as part of another group)" refers to a monovalent straight or branched chain saturated hydrocarbon group containing 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms. Alkyl is preferably a C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. In this application, alkyl is also intended to include substituted alkyls, i.e., one or more positions in the alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. "Haloalkyl" refers to an alkyl as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of haloalkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyls (e.g., -CF3), and the like.

[0228] "Alkylene" refers to a divalent radical of an alkyl group, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0229] "Alkoxy (alone or as part of another group)" refers to an alkyl group having an oxy group attached thereto, having an alkylO- structure, wherein alkyl has the definition described above. Preferably, alkoxy is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Haloalkoxy" refers to a group of the formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.

[0230] "Alkenyl (alone or as part of another group)" refers to an aliphatic group containing at least one double bond, typically having 2 to 20 carbon atoms. In the present invention, "C2-C6 alkenyl" refers to an alkenyl group containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

[0231] "Alkenylene" refers to an alkenyl group with two points of attachment. For example, "vinylene" refers to the group -CH=CH-. Alkenylene can also be unsubstituted or substituted with one or more substituents.

[0232] "Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing two or more carbon atoms and characterized by one or more triple bonds, typically having 2 to 20 carbon atoms. In the present invention, "C2-6 alkynyl" refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment for an alkynyl substituent. In the present invention, alkynyl groups also include substituted alkynyl groups.

[0233] "Alkynylene" refers to an alkynyl group with two points of attachment. For example, "ethynylene" refers to the group: -C≡C-. Alkynylene groups can be unsubstituted or substituted with one or more substituents.

[0234] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, and more preferably 3-8 ring atoms. A cycloalkyl group may be optionally substituted with one or more substituents, each of which is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0235] "Cycloalkyloxy" refers to a radical of the formula -OR, where R is a cycloalkyl radical as defined herein. Exemplary cycloalkyloxy radicals include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl" refers to a -(cycloalkyl)-alkyl radical where the cycloalkyl and alkyl radicals are as disclosed herein. "Cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl radical.

[0236] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8-10-membered) or tricyclic group of 5 to 12 ring atoms, which contains at least one aromatic ring containing 1, 2 or 3 ring heteroatoms selected from N, O or S, the remaining ring atoms being C, it being understood that the point of attachment of the heteroaryl group should be on the aromatic ring. Examples of heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl, pyranyl, pyridinyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine A heteroarylene group refers to a heteroaryl group having two attachment sites.

[0237] "Heterocyclic ring system" refers to monocyclic, bicyclic, and polycyclic ring systems in which at least one ring is saturated or partially unsaturated (but non-aromatic) and the ring contains at least one heteroatom. The heterocyclic ring system may be attached to a pendant group at any heteroatom or carbon atom that creates a stable structure and any ring atom may be optionally substituted.

[0238] "Heterocyclyl" refers to a monovalent radical of a heterocyclic ring system, generally a stable monocyclic ring (e.g., 3-8 members, i.e., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered) or bicyclic ring (e.g., 5-12 members, i.e., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered) or polycyclic ring (e.g., 7-14 members, i.e., 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered), including fused, spiro and / or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Representative heterocyclyl groups include ring systems in which (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl; (2) at least one ring is Non-aromatic and containing heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is aromatic and contains heteroatoms, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-naphthyridine. Heterocyclylene refers to a heterocyclyl having two connection sites. In the present invention, preferably, the heterocyclylene is a bicyclic ring, one of which is a heteroaryl group, and is connected to the other parts in the general formula through the heteroaryl group. In the present invention, preferably, the heterocyclylene is a 5-6 membered monocyclic heterocyclylene or an 8-10 membered bicyclic heterocyclylene.

[0239] "Heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined above.

[0240] When a substituent is a non-terminal substituent, it is a substituent of the corresponding group, for example, alkyl for alkylene, cycloalkyl for cycloalkylene, heterocyclyl for heterocyclylene, alkoxy for alkyleneoxy, and the like.

[0241] In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclyl, etc. may be substituted or unsubstituted.

[0242] In the present invention, the term "substituted" refers to one or more hydrogen atoms on a specific group being replaced by a specific substituent. The specific substituent is the substituent described above, or the substituent appearing in the embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. It will be understood by those skilled in the art that the combination of substituents contemplated by the present invention is those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a monohalogen substituent or a polyhalogen substituent, the latter such as a trifluoromethyl group or an alkyl group containing Cl3), cyano, nitro, oxo (such as =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocycle, aromatic ring, OR a SR a 、S(=O)R e 、S(=O)2R e 、P(=O)2R e 、S(=O)2OR e , P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e 、S(=O)2NR b R c 、P(=O)2NR b R c 、C(=O)OR d 、C(=O)R a 、C(=O)NR b R c 、OC(=O)R a 、OC(=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e , where Ra R may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings. b 、R c and R d may independently represent hydrogen, deuterium, an alkyl group, a cycloalkyl group, a heterocyclic ring or an aromatic ring, or R b and R c Together with the N atom, it can form a heterocyclic ring; R e and alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle, or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted. Examples of such substituents include, but are not limited to, halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, and C1-C6 urea.

[0243] "Cyano" refers to a -CN group.

[0244] "Nitro" refers to -NO2.

[0245] "Hydroxyl" refers to -OH.

[0246] "Amino" refers to -NH2 or RNH-, where R is ketocarbonyl, sulfonyl, sulfonamide, R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b is an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group.

[0247] "Halogen" refers to any halogen radical, for example, -F, -Cl, -Br, or -I.

[0248] "Deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0249] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0250] Compounds of formula I

[0251] The present invention provides a compound, which is a compound represented by Formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof.

[0252] Wherein, each group is as defined in the third aspect of the present invention.

[0253] In one embodiment, any one of the groups in the compound is independently the corresponding group in the specific compound.

[0254] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention formed with an acid or base that is suitable for pharmaceutical use. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are salts formed with a compound of the present invention and an acid. Suitable acids for forming salts include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0255] Another preferred salt is a salt of the compound of the present invention formed with a base, such as an alkali metal salt (e.g., sodium salt or potassium salt), an alkaline earth metal salt (e.g., magnesium salt or calcium salt), an ammonium salt (e.g., lower alkanolammonium salt and other pharmaceutically acceptable amine salts), for example, methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0256] The term "solvate" refers to a complex formed by the coordination of a compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of a compound of the present invention with water.

[0257] In addition, the compounds of the present invention also include prodrugs of the compounds represented by Formula I. The term "prodrug" includes compounds that may be biologically active or inactive, and that, when administered using appropriate methods, undergo metabolism or chemical reactions in the human body to transform into a compound of Formula I, or a salt or solution of a compound of Formula I. Such prodrugs include (but are not limited to) carboxylate esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compounds.

[0258] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0259] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0260] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0261] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (I) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0262] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0263] Specific functional groups and chemical term definitions are detailed below. For the purposes of this invention, chemical elements are referred to in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th The definitions of specific functional groups are consistent with those in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, which is incorporated by reference in its entirety.

[0264] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0265] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0266] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2H, due to its excellent metabolic stability, has advantages in certain therapies, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in certain circumstances. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents, using the protocols disclosed in the Examples.

[0267] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0268] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0269] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0270] It should be understood that the embodiments of the present invention specifically describe the preparation methods of the compounds of formula I of the present invention, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily made by those skilled in the art.

[0271] Typically, the raw materials and reagents used in the process for preparing the compounds of the present invention can be purchased through commercial channels unless otherwise specified.

[0272] Typically, in the preparation process, each reaction is usually carried out under the protection of an inert gas in a suitable solvent at a temperature of 0 to 150° C., and the reaction time is usually 2 to 24 hours.

[0273] Pharmaceutical compositions and methods of administration

[0274] The present invention also provides a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, and a pharmaceutically acceptable carrier.

[0275] Since the compounds of the present invention have excellent anti-tumor activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0276] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0277] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0278] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0279] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0280] The dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, film, pill, external ointment, controlled release or sustained release or nano preparation.

[0281] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0282] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0283] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0284] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0285] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0286] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0287] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0288] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0289] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0290] The compounds of Formula I may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the original drug's route of administration and dosage can remain unchanged, while the compound of Formula I is administered simultaneously or subsequently. When the compound of Formula I is administered concurrently with one or more other drugs, a pharmaceutical composition containing both the one or more known drugs and the compound of Formula I may be preferably used. Combination administration also includes administering the compound of Formula I and one or more other known drugs during overlapping time periods. When the compound of Formula I is administered in combination with one or more other drugs, the dosage of the compound of Formula I or the known drug may be lower than when administered alone.

[0291] Drugs or active ingredients that can be used in combination with the compound of Formula I include, but are not limited to, gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panitumumab, pertuzumab, zalutumumab, nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tanespiramycin, aspiramycin, IPI-504, and NVP-AUY922.

[0292] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human or mouse) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0293] Compared with the prior art, the main advantages of the present invention include:

[0294] (1) The compounds of the present invention have excellent EGFR degradation performance;

[0295] (2) The compounds of the present invention have excellent inhibitory and / or therapeutic effects on EGFR-related diseases, especially diseases with EGFR drug-resistant mutations, including but not limited to diseases selected from the group consisting of H1975 (T790M / L858R), HCC827 (19DEL), and PC-9 (19DEL);

[0296] (3) The compounds of the present invention have excellent pharmacokinetic properties;

[0297] (4) The compounds of the present invention are suitable for preventing and / or treating diseases selected from the group consisting of: cancers with EGFR-sensitive mutations, and diseases that develop secondary drug resistance during current EGFR treatments;

[0298] (5) The compounds of the present invention have excellent safety;

[0299] (6) The compounds of the present invention have excellent degradation selectivity for wild-type EGFR and mutant EGFR proteins, and have very good degradation efficiency for mutant EGFR proteins.

[0300] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0301] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0302] Example 1-1: Synthesis of Compound TA-003

[0303] Synthesis of intermediate compound M1

[0304] 1. Synthesis of Compound 2

[0305] In a 250 mL three-necked flask, 10 g of SM1, 10.7 g of boron trifluoride, 2.9 g of pd(dppf)Cl2, and 8.2 g of potassium carbonate were dissolved in 50 mL of 1,4-dioxane and 10 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 14.4 g of compound 2. LC-MS [M+1]: 198.

[0306] 2. Synthesis of compound 3

[0307] In a 100-mL three-necked flask, 2.7 g of compound 2, 4.3 g of 1-Boc-piperazine, and 9.4 g of potassium carbonate were dissolved in 27 mL of DMAC. The mixture was heated to 100°C under N2 protection and allowed to react overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with water and EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 3.8 g of compound 3. LC-MS [M+1]: 364.

[0308] 3. Synthesis of compound 4

[0309] In a 100 mL reactor, 3.8 g of compound 3 and 1.5 g of palladium on carbon were dissolved in 35 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 2.9 g of compound 4. LC-MS [M+1]: 336.

[0310] 4. Synthesis of intermediate M1

[0311] In a 100 ml reaction tube, 300 mg of compound 4, 265 mg of SM2, and 220 mg of p-toluenesulfonic acid monohydrate were dissolved in 3 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography to obtain 331 mg of intermediate M1. LC-MS [M+1]: 496.

[0312] Synthesis of intermediate compound M2

[0313] In a 250 mL three-necked flask, 8.3 g of SM1 was dissolved in 100 mL of dichloromethane. Triethylamine was added under N2 protection, and the temperature was lowered to 0°C in an ice bath. TF2O was slowly added dropwise and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. Water was added to the reaction solution and extracted with EA. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and subjected to column chromatography to obtain 2 g of intermediate M2.

[0314] Synthesis of intermediate compound M3

[0315] 1. Synthesis of Compound 2

[0316] In a 100 mL three-necked flask, 2 g of SM1, 2.2 g of pinacol diboronate, 2.4 g of pd(dppf)Cl2, and 1.7 g of potassium acetate were dissolved in 30 mL of 1,4-dioxane. Under nitrogen, the temperature was raised to 85°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 2 g of compound 2. LC-MS [M+1]: 389.

[0317] 2. Synthesis of compound 3

[0318] In a 250 mL three-necked flask, 2 g of compound 2, 2 g of intermediate M2, 1.5 g of sodium carbonate, and 376 mg of pd(dppf)Cl2 were dissolved in 40 mL of 1,4-dioxane and 10 mL of H2O. Under N2 protection, the temperature was raised to 55°C and the reaction was allowed to proceed for 2 h. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was then extracted with dichloromethane and the organic phase was washed once with saturated NaCl and dried. The sample was then spin-dried and purified by column chromatography to yield 1.8 g of compound 3. LC-MS [M+1]: 480.

[0319] 3. Synthesis of compound 4

[0320] In a 100 mL single-necked flask, 1.8 g of compound 3 was dissolved in 18 mL of ethyl acetate. 1,4-dioxane hydrochloride was added and the mixture was allowed to react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was filtered to obtain 1 g of a filter cake, which was compound 4. LC-MS [M+1]: 380.

[0321] 4. Synthesis of Compound 5

[0322] In a 100-mL three-necked flask, 1 g of compound 4 was dissolved in 10 mL of DMF. Under nitrogen, 2 mL of N,N-diisopropylethylamine was added. After stirring for 10 min in an ice bath, 0.4 mL of tert-butyl bromoacetate was added. The reaction was allowed to react overnight at room temperature. Completion of the reaction was monitored by TLC. Water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by column chromatography to yield 1.5 g of compound 5. LC-MS [M+1]: 494.

[0323] 5. Synthesis of Compound 6

[0324] In a 100 mL reactor, 1.5 g of compound 5 and 228 mg of palladium on carbon were dissolved in 30 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 200 mg of compound 6. LC-MS [M+1]: 496.

[0325] 6. Synthesis of intermediate M3

[0326] In a 100 mL reaction tube, 200 g of compound 6 was added and dissolved in 1 mL of dichloromethane. 0.2 mL of trifluoroacetic acid was added and the mixture was reacted at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was concentrated to remove the solvent to obtain 283 mg of intermediate M3. LC-MS [M+1]: 440.

[0327] Synthesis of compound TA-003

[0328] In a 100 mL reaction tube, 98 mg of compound M1 and 139 mg of compound M3 were dissolved in 1 mL of NN-dimethylformamide. The mixture was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine and HATU were added with stirring. The mixture was reacted in an ice-water bath under nitrogen for 1 hour. The temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was detected to be complete by TLC. The mixture was extracted with dichloromethane and water. The organic phase was dried and purified by column chromatography to obtain 80 mg of compound TA-003. LC-MS [M+1]: 917.8.

[0329] 1H NMR (400MHz, DMSO) δ11.62(s,1H),10.60(s,1H),8.73(d,J=4.4Hz,1H),8.57(d,J=7.0Hz,1H),8.23(s,1H),8.14(s,1H),7.69(t,J=5.8Hz,2H) ,7.50(s,1H),7.43(d,J=10.4Hz,1H),7.31(t,J=7.5Hz,1H),7.05(t,J=7.5Hz,1H),6.82(s,1H),3.99(s,3H),3.91(t,J=6.7Hz,2H),3.75(s,6 H),3.59(s,2H),3.49(d,J=15.4Hz,3H),3.06(d,J=10.3Hz,1H),2.92(s,1H),2.89(s,1H),2.83(d,J=5.1Hz,2H),2.80(d,J=4.4Hz,3H),2.75( dd,J=12.1,5.6Hz,3H),2.63(dd,J=14.7,7.3Hz,2H),2.58–2.53(m,1H),2.39(d,J=12.0Hz,1H),1.86(d,J=11.9Hz,1H),1.10(t,J=7.4Hz,3H).

[0330] Referring to the synthesis method of intermediate compound M1 and the synthesis method of compound TA-003, the following compounds were synthesized respectively:

[0331] Example 1-2: Synthesis of Compound TA-005

[0332] Synthesis of intermediate compound M1

[0333] In a 100-mL single-necked flask, dissolve 500 mg of (2-aminophenyl)dimethylphosphine oxide in 10 mL of isopropanol. Add 0.7 mL of 2,4,5-trichloropyrimidine and 2.9 mL of DIPEA sequentially. Under nitrogen, heat to 100°C and allow to react overnight. Monitor completion by TLC. The reaction mixture is then directly dried and sampled. Column chromatography yields 1 g of intermediate M1. LC-MS [M+1]: 317.

[0334] Synthesis of intermediate compound M2

[0335] 1. Synthesis of Compound 2

[0336] In a 250 mL three-necked flask, 8.4 g of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 5.3 g of compound 2. LC-MS [M+1]: 198.

[0337] 2. Synthesis of compound 3

[0338] In a 250 mL three-necked flask, 4.8 g of compound 2, 6.9 g of 1-Boc-piperazine, and 16.8 g of potassium carbonate were dissolved in 48 mL of DMAC. The mixture was heated to 100°C under N2 protection and allowed to react overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with water and EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and subjected to column chromatography to obtain 6.5 g of compound 3. LC-MS [M+1]: 364.

[0339] 3. Synthesis of compound 4

[0340] In a 100 mL reactor, 6.5 g of compound 3 and 1.3 g of palladium on carbon were dissolved in 70 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 5.6 g of compound 4. LC-MS [M+1]: 336.

[0341] 4. Synthesis of intermediate M2

[0342] In a 100 ml reaction tube, 200 mg of compound 4, 188 mg of intermediate M1, and 147 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography was performed to obtain 136 mg of intermediate M2. LC-MS [M+1]: 515.

[0343] Synthesis of compound TA-005

[0344] In a 100 mL reaction tube, 105 mg of compound M2 and 144 mg of the intermediate compound M3 in Example 1-1 were dissolved in 1 mL of NN-dimethylformamide. The mixture was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine and HATU were added with stirring. The mixture was reacted in an ice-water bath under nitrogen for 1 hour. The temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was detected to be complete by TLC. The mixture was extracted with dichloromethane and water. The organic phase was dried and purified by column chromatography to obtain 18 mg of compound TA-005, LC-MS [M+1]: 936.

[0345] 1 H NMR (400MHz, DMSO) δ11.13(s,1H),10.59(s,1H),8.42(s,1H),8.18(s,1H),8.11(s,1H),7.69(d,J=5.3Hz,1H),7.53–7.41 (m,3H),7.31(d,J=7.8Hz,1H),7.05(t,J=7.3Hz,1H),6.81(s,1H),3.98(s,3H),3.91(t,J=6.7Hz,2H),3.75(s,4H),3.25( s,2H),3.06(d,J=9.3Hz,2H),2.90(s,2H),2.83(s,2H),2.76(t,J=6.7Hz,3H),2.59(dt,J=17.8,8.8Hz,3H),2.43–2.30(m ,2H),2.03–1.93(m,1H),1.88(s,1H),1.76(d,J=13.5Hz,6H),1.35–1.28(m,1H),1.20–1.14(m,1H),1.09(t,J=7.5Hz,3H).

[0346] The following compounds were synthesized by referring to the method of Example 1-2:

[0347] The following chiral compounds were obtained by high pressure preparative chromatography:

[0348] Example 1-3: Synthesis of Compound TC-159

[0349] Synthesis of intermediate compound M1

[0350] 1. Synthesis of Compound 2

[0351] In a 50 mL three-necked flask, 500 mg of compound 1, 917 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787 mg of sodium carbonate, and 181 mg of pd(dppf)Cl2 were dissolved in 10 mL of 1,4-dioxane and 1 ml of H2O. The mixture was heated to 80°C under N2 protection and allowed to react overnight. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was added with water and extracted with dichloromethane. The organic phase was washed once with saturated NaCl and dried. The sample was then spin-dried and subjected to column chromatography to obtain 300 mg of compound 2. LC-MS [M+1]: 305

[0352] 2. Synthesis of compound 3

[0353] In a 50mg single-necked bottle, 300mg of compound 2, 15mg of palladium-carbon catalyst, and 4ml of methanol were added and mixed. The mixture was ventilated three times with a hydrogen balloon and maintained. After reacting at room temperature overnight, TLC detected that the reaction was complete. The palladium-carbon was removed by filtration through a celite pad, and the mother liquor was dried to obtain 100mg of compound 3.

[0354] 3. Synthesis of intermediate M1

[0355] In a 100-ml reaction flask, 103 mg of compound SM1, 100 mg of compound 3, and 81 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography to obtain 50 mg of intermediate M1. LC-MS [M+1]: 486.

[0356] Synthesis of compound TC-159

[0357] Referring to the synthesis method of TA-003 in Example 1-1, the intermediate M3 in Example 1-1 was used to synthesize compound TC-159. LC-MS [M+1]: 907.6. Example 1-4

[0358] Synthesis of intermediate compound M1

[0359] 1. Synthesis of Compound 2

[0360] 735 mg of SM1, 317 mg of dimethyl phosphine oxide, 12 ml of DMF, and 3 ml of water were added to a 100 ml single-necked bottle, mixed, and replaced with nitrogen. 862 mg of potassium phosphate, 60 mg of palladium acetate, and 151 mg of Xantphos were added under nitrogen protection. The reaction was carried out at 120°C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column chromatography to obtain 283 mg of compound 2.

[0361] 2. Synthesis of intermediate compound M1

[0362] In a 100-mL single-necked flask, 140 mg of compound 2 was dissolved in 3 mL of isopropanol. 0.14 mL of 2,4,5-trichloropyrimidine and 0.6 mL of DIPEA were added sequentially. Under N₂ protection, the temperature was raised to 100°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The reaction solution was then directly dried and sampled. Column chromatography yielded 81 mg of intermediate M1. LC-MS [M+1]: 368.

[0363] Synthesis of intermediate compound M2

[0364] In a 100 ml reaction tube, 81 mg of compound M1, 74 mg of intermediate SM2, and 54 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography to yield 76 mg of intermediate M2. LC-MS [M+1]: 567.

[0365] Synthesis of compound TA-007

[0366] Referring to the synthesis method of TA-003 in Example 1-1, compound TA-007 was synthesized using intermediate M3 in Example 1-1. LC-MS [M+1]: 988.7.

[0367] Example 1-5: Synthesis of Compound TA-015

[0368] Synthesis of intermediate compound M1

[0369] 1. Synthesis of Compound 2

[0370] In a 250ml single-necked flask, add 3.8g of compound 1, 5.2ml of isopropyl pinacol ester, and 95ml of tetrahydrofuran, stirring to dissolve. Cool in an ice-water bath for 10 minutes, and slowly add 12ml of isopropyl magnesium chloride dropwise. After reacting at room temperature for 2 hours, quench with water, extract with ethyl acetate, and purify by column chromatography to obtain 3.4g of compound 2.

[0371] 2. Synthesis of intermediate M1

[0372] To a 250ml three-necked flask, 3.4g of compound 2, 2.53g of trichloropyrimidine, 2.94g of sodium carbonate, 85ml of acetonitrile, and 17ml of water were added. Stirring was continued, and 1g of tetrakistriphenylphosphine palladium was added under nitrogen. The reaction was allowed to proceed overnight at 80°C. Column purification was performed to obtain 1.7g of intermediate M1.

[0373] Synthesis of intermediate compound M2

[0374] M2 was synthesized by referring to the synthesis method of intermediate M2 in Example 3. LC-MS [M+1]: 463.

[0375] Synthesis of compound TA-015

[0376] Compound TA-015 was synthesized by referring to the synthesis method of TA-003 in Example 1-1. LC-MS [M+1]: 855.6.

[0377] Example 1-6: Synthesis of Compound TA-039

[0378] Synthesis of intermediate compound M1

[0379] 1. Synthesis of Compound 2

[0380] In a 100 ml single-necked bottle, 1 g of compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane were added, mixed, and replaced with nitrogen. Then, 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos were added under nitrogen protection. The reaction was carried out at 80°C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column chromatography to obtain 705 mg of compound 2.

[0381] 2. Synthesis of compound 3

[0382] In a 100 ml single-necked bottle, 500 mg of compound 2, 520 mg of cyclopropylboronic acid, 5 ml of dioxane, and 1 ml of water were added, mixed, and then replaced with nitrogen. Then, 1.7 g of potassium phosphate, 45 mg of palladium acetate, and 113 mg of tricyclohexylphosphine were added under nitrogen protection. The reaction was carried out at 80 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column to obtain 151 mg of compound 3.

[0383] 3. Synthesis of intermediate M1

[0384] In a 250 ml three-necked flask, 100 mg of compound 3, 176 mg of trichloropyrimidine, 199 mg of potassium carbonate, and 2 ml of DMF were added. After stirring, the mixture was stirred under nitrogen and allowed to react overnight at 100°C. Column purification was performed to obtain 93 mg of intermediate M1.

[0385] Synthesis of compound TA-039

[0386] Referring to the synthesis method of TA-003 in Example 1-1, compound TA-039 was synthesized using intermediate M3 in Example 1-1. LC-MS [M+1]: 977.

[0387] The following compounds were synthesized by referring to the methods of Examples 1-6:

[0388] Comparative Example 1-1: Synthesis of Comparative Example Compound C1

[0389] Synthesis of intermediate compound M1

[0390] The synthetic route is as follows:

[0391] Intermediate M1 was synthesized by referring to the synthesis method of intermediate M1 in Example 1-1.

[0392] Synthesis of intermediate compound M2

[0393] The synthetic route is as follows:

[0394] 1. Synthesis of Compound 2

[0395] In a 100 ml single-necked flask, compound 1 (1.0 g, 1.0 eq) was mixed with pinacol diboronate (1.18 g, 1.2 eq), 15 ml of 1,4-dioxane, potassium acetate (911 mg, 3.0 eq), and PdCl2dppf (113 mg, 0.12 eq). After nitrogen replacement, the mixture was heated to 85°C and allowed to react overnight. TLC monitored the reaction until completion. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to yield 1.2 g of compound 2. LC-MS [M+1]: 372.

[0396] 2. Synthesis of compound 3

[0397] In a 100ml three-necked flask, 400mg of compound 2 (1.2 equivalents), 484mg of SM1 (1.0 equivalents), 345mg of potassium carbonate (3.0 equivalents), 10ml of 1,4-dioxane, and 2.5ml of water were mixed thoroughly under nitrogen. 80mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.12 equivalents) was added, and the temperature was raised to 55°C for 2 hours. The reaction was monitored by TLC until completion, filtered through a pad of Celite, and the mother liquor was collected. The solvent was removed by rotary evaporation, followed by addition of 30ml of water and extraction three times with 15ml of ethyl acetate. The combined organic phases were mixed and passed through a column chromatography column to yield 500mg of compound 3. LC-MS [M+1]: 462.

[0398] 3. Synthesis of compound 4

[0399] Compound 3 (500 mg, 1.0 eq), palladium-carbon catalyst (50 mg, 5 wt%), and 5 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then replaced with a hydrogen balloon three times, and the pressure was maintained at room temperature for 20 hours. TLC indicated complete reaction. The reaction was then filtered through a celite pad, and the mother liquor was collected to yield 400 mg of compound 4.

[0400] 4. Synthesis of Compound 5

[0401] To a 100 ml single-necked flask, add 400 mg of compound 4 and dissolve in 10 ml of tetrahydrofuran. Cool in an ice-water bath and add dropwise a 4 M solution of dioxane hydrochloride. After addition, react at 40°C for 2 hours. Remove the solvent by rotary evaporation to obtain 330 mg of compound 5. LC-MS [M+1]: 364.

[0402] 5. Synthesis of Compound 6

[0403] To a 100 ml single-necked flask, 330 mg of compound 5, 4 ml of NN-dimethylformamide, 1.2 ml of NN-diisopropylethylamine (5.0 eq), and tert-butyl bromoacetate (195 mg, 1.1 eq) were added and stirred at room temperature overnight. TLC confirmed the reaction was complete, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and purified by column chromatography to yield 370 mg of compound 6. LC-MS [M+1]: 479.

[0404] 6. Synthesis of intermediate M2

[0405] In a 100 ml single-necked flask, 350 mg of compound 6 and 3 ml of dichloromethane were added dropwise, and 2 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight. The reaction was detected to be complete by TLC. The solvent was removed by rotary evaporation to obtain 150 mg of M2, LC-MS [M-1]: 420.

[0406] Comparative Example 1-1 Synthesis of Compound C1

[0407] The synthetic route is as follows:

[0408] Compounds M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml of NN-dimethylformamide in a 50 ml round-bottom flask and cooled to 0°C in an ice-water bath. NN-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added with stirring. The mixture was reacted in an ice-water bath under nitrogen for 1 hour. The temperature was naturally raised to room temperature. The reaction was determined to be complete by TLC. The mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and purified by column chromatography to obtain 90 mg of reference compound C1. LC-MS [M+1]: 899.6.

[0409] 1H NMR(400MHz,DMSO-d6)δ11.69(s,1H),10.64(s,1H),8.80(s,1H),8.70– 8.54(m,1H),8.29(s,1H),8.21(s,1H),7.76(d,J=7.8Hz,1H),7.71–7.52(m,3H),7.38(s,1H),7 .13(q,J=8.5,7.6Hz,2H),6.88(s,1H),4.12–3.93(m,6H),3.79(d,J=18.4Hz,5H),3.68(s,3H),3 .53–3.51(m,1H),3.20(d,J=7.6Hz,2H),3.10(s,1H),2.98(s,2H),2.93–2.78(m,8H),2.69(d,J =7.4Hz,1H),2.33(d,J=12.9Hz,1H),2.05(s,1H),1.94(d,J=13.0Hz,1H),1.16(t,J=7.6Hz,3H).

[0410] Intermediate preparation example:

[0411] Synthesis of intermediate INT-1

[0412] In a 100-mL single-necked flask, dissolve 500 mg of (2-aminophenyl)dimethylphosphine oxide in 10 mL of isopropanol. Add 0.7 mL of 2,4,5-trichloropyrimidine and 2.9 mL of DIPEA sequentially. Under nitrogen, heat to 100°C and allow to react overnight. Monitor the reaction by TLC until completion. The reaction mixture is then directly dried and sampled. Column chromatography yields 1 g of intermediate INT-1. LC-MS [M+1]: 317.

[0413] Synthesis of intermediate compound INT-2

[0414] 1. Synthesis of Compound 2

[0415] In a 250 mL three-necked flask, 8.4 g of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 5.3 g of compound 2. LC-MS [M+1]: 198.

[0416] 2. Synthesis of compound 3

[0417] In a 250 mL three-necked flask, 4.8 g of compound 2, 6.9 g of 1-Boc-piperazine, and 16.8 g of potassium carbonate were dissolved in 48 mL of DMAC. The mixture was heated to 100°C under N2 protection and allowed to react overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with water and EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and subjected to column chromatography to obtain 6.5 g of compound 3. LC-MS [M+1]: 364.

[0418] 3. Synthesis of intermediate INT-2

[0419] In a 100 mL reactor, 6.5 g of compound 3 and 1.3 g of palladium on carbon were dissolved in 70 mL of methanol under a hydrogen atmosphere. The reaction was allowed to proceed overnight at room temperature. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography was performed to obtain 5.6 g of intermediate INT-2. LC-MS [M+1]: 336.

[0420] Synthesis of intermediate INT-3

[0421] 1. Synthesis of Compound 2

[0422] In a 50 mL three-necked flask, 500 mg of compound 1, 917 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787 mg of sodium carbonate, and 181 mg of pd(dppf)Cl2 were dissolved in 10 mL of 1,4-dioxane and 1 ml of H2O. The mixture was heated to 80°C under N2 protection and allowed to react overnight. TLC showed that the starting material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was added with water and extracted with dichloromethane. The organic phase was washed once with saturated NaCl and dried. The sample was then spin-dried and subjected to column chromatography to obtain 300 mg of compound 2. LC-MS [M+1]: 305

[0423] 2. Synthesis of intermediate IN-3

[0424] In a 50mg single-necked bottle, 300mg of compound 2, 15mg of palladium carbon catalyst, and 4ml of methanol were added and mixed. The mixture was ventilated three times with a hydrogen balloon and maintained. After reacting at room temperature overnight, TLC detected that the reaction was complete. The palladium carbon was removed by filtration on a diatomaceous earth pad, and the mother liquor was dried to obtain 100mg of intermediate INT-3.

[0425] Synthesis of intermediate compound INT-4

[0426] 1. Synthesis of Compound 2

[0427] 735 mg of SM1, 317 mg of dimethyl phosphine oxide, 12 ml of DMF, and 3 ml of water were added to a 100 ml single-necked bottle, mixed, and replaced with nitrogen. 862 mg of potassium phosphate, 60 mg of palladium acetate, and 151 mg of Xantphos were added under nitrogen protection. The reaction was carried out at 120°C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column chromatography to obtain 283 mg of compound 2.

[0428] 2. Synthesis of intermediate compound INT-4

[0429] In a 100-mL single-necked flask, 140 mg of compound 2 was dissolved in 3 mL of isopropanol. 0.14 mL of 2,4,5-trichloropyrimidine and 0.6 mL of DIPEA were added sequentially. Under N₂ protection, the temperature was raised to 100°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The reaction solution was then directly dried and the sample was purified by column chromatography to yield 81 mg of intermediate INT-4. LC-MS [M+1]: 368.

[0430] Synthesis of intermediate compound INT-5

[0431] 1. Synthesis of Compound 2

[0432] In a 100 ml single-necked bottle, 1 g of compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane were added, mixed, and replaced with nitrogen. Then, 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos were added under nitrogen protection. The reaction was carried out at 80°C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column chromatography to obtain 705 mg of compound 2.

[0433] 2. Synthesis of compound 3

[0434] In a 100 ml single-necked bottle, 500 mg of compound 2, 520 mg of cyclopropylboronic acid, 5 ml of dioxane, and 1 ml of water were added, mixed, and then replaced with nitrogen. Then, 1.7 g of potassium phosphate, 45 mg of palladium acetate, and 113 mg of tricyclohexylphosphine were added under nitrogen protection. The reaction was carried out at 80 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, the mixture was purified by column to obtain 151 mg of compound 3.

[0435] 3. Synthesis of intermediate INT-5

[0436] In a 250ml three-necked flask, 100mg of compound 3, 176mg of trichloropyrimidine, 199mg of potassium carbonate, and 2ml of DMF were added. The mixture was stirred evenly and then nitrogen atmosphere was applied. The reaction was allowed to proceed overnight at 100°C. Column purification was performed to obtain 93mg of the intermediate INT-5.

[0437] Synthesis of intermediate compound INT-6

[0438] In a 250 mL three-necked flask, 8.3 g of SM1 was dissolved in 100 mL of dichloromethane. Triethylamine was added under N2 protection, and the temperature was lowered to 0°C in an ice bath. TF2O was slowly added dropwise and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until completion. Water was added to the reaction solution and extracted with EA. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and subjected to column chromatography to obtain 2 g of intermediate INT-6.

[0439] Synthesis of intermediate compound INT-7

[0440] Synthesis of compound 2

[0441] In a 250 ml single-necked bottle, 6.7 g SM1, 15.2 ml 1,2-dibromoethane, and 14.5 g potassium carbonate were added and dissolved in 67 ml ACN. The mixture was heated at 85°C and reacted overnight. After TLC showed that the reaction was complete, the reaction solution was cooled to room temperature and then dried by column drying to obtain 8.47 g of compound 2.

[0442] Synthesis of compound 3

[0443] To a 250ml three-necked flask, add 3g of compound 2, dissolve it in 38ml of THF, and then, under nitrogen, cool it from -80°C to -78°C. Slowly add 4ml of n-butyllithium dropwise. After the addition is complete, continue the reaction at -78°C for 2h and stir at room temperature overnight. After TLC, the reaction is complete, quench with ammonium chloride in an ice bath, remove the organic solvent, and extract with ethyl acetate. The organic phase is dried and then filtered through a column to obtain 1.2g of compound 3 as a colorless oil.

[0444] Synthesis of compound 4

[0445] 1.2 g of compound 3 was added to a 100 ml single-necked flask and dissolved in 12 ml of ACN. The mixture was stirred under nitrogen atmosphere for 10 min under an ice bath. 1.7 g of NBS was added and stirred at room temperature for 2 h. After the reaction, 1.6 g of compound 4 was obtained by column chromatography.

[0446] Synthesis of compound 5

[0447] In a 100ml single-necked flask, 1.6g of compound 4 was dissolved in 13ml of TFA. The mixture was stirred under nitrogen atmosphere for 10 minutes under an ice bath. Sodium nitrite was added and the mixture was allowed to warm to room temperature overnight. After completion of the reaction by TLC, the TFA was removed by concentration. The remaining solution was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to yield 874mg of compound 5.

[0448] Synthesis of compound 6

[0449] To a 10ml reaction tube, 874mg of compound 5, 212mg of N-Boc piperazine, and 210mg of potassium carbonate were added. The mixture was dissolved in 4ml of DMF and heated at 65°C overnight under nitrogen. After TLC analysis of the reaction, the reaction solution was cooled to room temperature, water was added, and extraction with ethyl acetate was performed. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to yield 189mg of compound 6.

[0450] Synthesis of compound 7

[0451] To a 10ml reaction tube, 189mg of compound 6, 118mg of C2H3BF3K, 91mg of potassium carbonate, and 32mg of Pd(dppf)Cl2 were added. Dissolved in 2ml of 1,4-dioxane, and then 0.4ml of water was added. Under nitrogen protection, the mixture was heated at 100°C for 4 hours. After TLC analysis, the reaction solution was cooled to room temperature and purified by column chromatography to yield 135mg of compound 7.

[0452] Synthesis of intermediate INT-7

[0453] In a 10 ml reaction tube, 135 mg of compound 7 and 13 mg of palladium on carbon were added, dissolved in 3 ml of methanol, and reacted overnight at room temperature under hydrogen atmosphere. After TLC analysis, the palladium on carbon was removed by filtration, and the filtrate was concentrated to obtain 137 mg of INT-7.

[0454] Synthesis of intermediate compound INT-8

[0455] Synthesis of compound 2

[0456] In a 100ml single-necked flask, 1g SM1, 0.83g tert-butyl bromoacetate, 2.2g cesium carbonate, and 10ml acetonitrile were added. The temperature was raised to 55°C under nitrogen and the reaction was continued for 7 hours. After TLC indicated the reaction was complete, the solvent was removed by rotary evaporation and the sample was passed through a column to obtain 1.4g of a light yellow oil, Compound 2.

[0457] Synthesis of compound 3

[0458] In a 100ml single-necked bottle, add 200mg of SM2, 257mg of compound 2, 381mg of cesium carbonate, 64mg of Pd(dppf)Cl2, 10ml of 1,4-dioxane, and 1ml of water. Heat to 90°C under nitrogen and react overnight. After TLC showed completion of the reaction, the product was directly purified by column chromatography to yield 100mg of compound 3. LC-MS [M+1]: 471

[0459] Synthesis of compound INT-8

[0460] Dissolve 100 mg of compound 3 in 4 ml of dichloromethane in a 50 ml single-necked bottle, slowly add 1 ml of trifluoroacetic acid, and react at room temperature for 3 hours. The reaction solution is spin-dried and used as a crude product in the next step.

[0461] Synthesis of intermediate compound INT-9

[0462] Synthesis of compound 2

[0463] In a 250ml single-necked bottle, 5g of compound 1 and 5ml of ammonia water were heated at 120°C in 10ml of n-butanol and reacted overnight. After TLC showed that the reaction was complete, water and ethyl acetate were added to extract the reaction solution. The organic phases were combined and dried by column chromatography to obtain 3.8g of compound 2.

[0464] Synthesis of compound 3

[0465] In a 100ml single-necked flask, mix 1g of compound 2 and 640mg of phthalic anhydride. Heat to 170°C and stir in the molten state for 6 hours. Remove from heat, cool to room temperature, add 20ml of a 1:1 mixture of dichloromethane and methanol, and stir at room temperature for 30 minutes. Collect the filter cake by suction to yield 1.3g of a white solid.

[0466] Synthesis of compound 4

[0467] In a 100ml single-necked flask, add 1g of compound 3, 510mg of phenylboronic acid, 750mg of copper acetate, 0.5ml of pyridine, and 50ml of dichloromethane. After mixing, replace the mixture with an oxygen balloon three times. Maintain an oxygen atmosphere and allow the reaction to proceed overnight. After TLC indicates the reaction is complete, the mother liquor is collected by filtration, dried, and purified by column to obtain 200mg of compound 4. LC-MS: 436

[0468] Synthesis of compound 5

[0469] In a 50ml single-necked flask, add 200mg of compound 4, 10ml of ammonia water, and 10ml of methanol, and stir at room temperature overnight. After TLC shows the reaction is complete, remove the methanol by rotary evaporation, extract the reaction solution with ethyl acetate, and combine the organic phases and purify them by column chromatography to obtain 110mg of a white solid. LCMS: 306 / 308

[0470] Synthesis of compound 6

[0471] Mix 150 mg of compound 5 and 53 mg of acrylic acid in 5 ml of 2N hydrochloric acid, then add 16 mg of tetrabutylammonium bromide. Heat to 100°C under nitrogen and allow to react overnight. After TLC indicates the reaction is complete, cool to room temperature and adjust the pH to 7-8 with a saturated sodium bicarbonate solution in an ice-water bath. Adjust the pH to 5-6 with acetic acid. A large amount of solid precipitates, collecting the filter cake (150 mg) by filtration. LCMS: 378

[0472] Synthesis of compound 7

[0473] Mix 150 mg of compound 6, 56 mg of sodium cyanate, and 1.5 ml of acetic acid. Heat to 60°C and allow to react overnight. Add 1.5 ml of 2N hydrochloric acid and maintain for 3 hours. Turn off the heat and allow the mixture to cool to room temperature. A solid precipitates and the filter cake is collected by filtration to yield 80 mg of compound 7.

[0474] Synthesis of compound 8

[0475] 500 mg of compound 7, 632 mg of pinacol diboronate, 1.2 g of potassium acetate, and 45 mg of Pd(dppf)Cl2 were evenly dispersed in 1.4-dioxane. After nitrogen replacement three times, the mixture was heated to 80°C and reacted overnight under nitrogen protection. TLC indicated complete reaction of the starting materials. The sample was then directly separated by column chromatography to yield 560 mg of compound 8. LC-MS: 451.

[0476] Synthesis of compound 9

[0477] 560 mg of compound 8, 538 mg of M3 from Example 2, 404 mg of sodium carbonate, and 100 mg of Pd(dppf)Cl2 were uniformly dispersed in 6 ml of 1,4-dioxane and 0.6 ml of water. After nitrogen replacement, the mixture was heated to 55°C under nitrogen protection and reacted for 2 hours.

[0478] When TLC showed no starting material, the reaction was terminated, and the reaction solution was spin-dried and purified by column to obtain 340 mg of compound 9. LC-MS: 542

[0479] Synthesis of compound 10

[0480] Disperse 340 mg of compound 9 in 6 ml of ethyl acetate and add 1.6 ml of hydrochloric acid / 1,4-dioxane. React at room temperature for 4 hours. LC-MS shows no residual starting material. The reaction solution is then dried and used in the next step.

[0481] Synthesis of compound 11

[0482] 380 mg of compound 10, 53 mg of tert-butyl bromoacetate, and 0.2 ml of DIPEA were dissolved in 2 ml of DMF and reacted at room temperature overnight. After TLC showed that the reaction was complete, the reaction solution was extracted with ethyl acetate, and the organic phases were combined and passed through a column to obtain 350 mg of compound 11. LC-MS: 556

[0483] Synthesis of compound 12

[0484] 300 mg of compound 11 was added with 60 mg of palladium-carbon catalyst, 3 ml of methanol, and 3 ml of ethyl acetate. The mixture was then replaced with hydrogen three times. A hydrogen balloon was sealed and the reaction was carried out at 35°C overnight. TLC showed that the reaction was complete. Filtered on celite pad, the mother liquor was collected, dried and passed through a column to obtain 170 mg of compound 12. LCMS: 558

[0485] Synthesis of compound INT-9

[0486] 170 mg of compound 12 was dissolved in 2 ml of dichloromethane, 1.7 ml of trifluoroacetic acid was added dropwise, and the mixture was reacted at room temperature for 3 hours. After the reaction, the mixture was dried and dried to obtain 150 mg of compound INT-9.

[0487] Synthesis of intermediate INT-10

[0488] The synthetic route is as follows:

[0489] 1. Synthesis of Compound 2

[0490] In a 100 ml single-necked flask, compound 1 (1.0 g, 1.0 eq) was mixed with pinacol diboronate (1.18 g, 1.2 eq), 15 ml of 1,4-dioxane, potassium acetate (911 mg, 3.0 eq), and PdCl2dppf (113 mg, 0.12 eq). After nitrogen replacement, the mixture was heated to 85°C and allowed to react overnight. TLC monitored the reaction until completion. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and separated by column chromatography to yield 1.2 g of compound 2. LC-MS [M+1]: 372.

[0491] 2. Synthesis of compound 3

[0492] In a 100ml three-necked flask, 400mg of compound 2 (1.2 equivalents), 484mg of SM1 (1.0 equivalents), 345mg of potassium carbonate (3.0 equivalents), 10ml of 1,4-dioxane, and 2.5ml of water were mixed thoroughly under nitrogen. 80mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.12 equivalents) was added, and the temperature was raised to 55°C for 2 hours. The reaction was monitored by TLC until completion, filtered through a pad of Celite, and the mother liquor was collected. The solvent was removed by rotary evaporation, followed by addition of 30ml of water and extraction three times with 15ml of ethyl acetate. The combined organic phases were mixed and passed through a column chromatography column to yield 500mg of compound 3. LC-MS [M+1]: 462.

[0493] 3. Synthesis of compound 4

[0494] Compound 3 (500 mg, 1.0 eq), palladium-carbon catalyst (50 mg, 5 wt%), and 5 ml of methanol were added to a 50 ml single-necked flask and mixed thoroughly. The mixture was then replaced with a hydrogen balloon three times, and the pressure was maintained at room temperature for 20 hours. TLC indicated complete reaction. The reaction was then filtered through a celite pad, and the mother liquor was collected to yield 400 mg of compound 4.

[0495] 4. Synthesis of Compound 5

[0496] To a 100 ml single-necked flask, add 400 mg of compound 4 and dissolve in 10 ml of tetrahydrofuran. Cool in an ice-water bath and add dropwise a 4 M solution of dioxane hydrochloride. After addition, react at 40°C for 2 hours. Remove the solvent by rotary evaporation to obtain 330 mg of compound 5. LC-MS [M+1]: 364.

[0497] 5. Synthesis of Compound 6

[0498] To a 100 ml single-necked flask, 330 mg of compound 5, 4 ml of NN-dimethylformamide, 1.2 ml of NN-diisopropylethylamine (5.0 eq), and tert-butyl bromoacetate (195 mg, 1.1 eq) were added and stirred at room temperature overnight. TLC confirmed the reaction was complete, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and purified by column chromatography to yield 370 mg of compound 6. LC-MS [M+1]: 479.

[0499] 6. Synthesis of intermediate INT-10

[0500] In a 100 ml single-necked flask, 350 mg of compound 6 and 3 ml of dichloromethane were added dropwise, and 2 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight. The reaction was detected to be complete by TLC. The solvent was removed by rotary evaporation to obtain 150 mg of INT-10, LC-MS [M-1]: 420.

[0501] Synthesis of intermediate compound INT-11

[0502] The synthetic route is as follows:

[0503] 1. Synthesis of Compound 2

[0504] In a 250 mL three-necked flask, 8.4 g of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 5.3 g of compound 2. LC-MS [M+1]: 198.

[0505] 2. Synthesis of Compound 3

[0506] To a 50ml single-necked flask, add 1g of compound 2, 1.7g of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate, and 2.1g of potassium carbonate. Dissolve in 10ml of dimethylacetamide, then under nitrogen atmosphere. Heat at 110°C for 5h. After TLC analysis of the reaction, cool the reaction mixture to room temperature, add water, and extract with ethyl acetate. The organic phase is washed twice with saturated brine, dried, concentrated, and filtered to yield 6g of compound 3 as a yellow solid. LC-MS [M+1]: 404.

[0507] 3. Synthesis of Intermediate INT-11

[0508] To a 100ml single-necked flask, add 6g of compound 3 and 60mg of palladium on carbon. Dissolve in 60ml of anhydrous ethanol and allow to react at room temperature under a hydrogen atmosphere. After completion of the reaction, remove the palladium on carbon by filtration, and concentrate the filtrate to yield 1.9g of intermediate INT-11. LC-MS [M+1]: 376.

[0509] Synthesis of intermediate compound INT-12

[0510] Synthesis of compound 2

[0511] 1.15 g of tert-butyl acetate and 20 ml of dry tetrahydrofuran were mixed evenly and then protected with nitrogen. The temperature was lowered to -78 °C, and 11.8 ml of LDA was slowly added dropwise. The temperature was kept for half an hour. A dilution of 3 g of SM1 in 20 ml of tetrahydrofuran was added dropwise again, and the temperature was kept at low temperature for 1 hour. After the reaction, the reaction solution was quenched with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic phase was dried and filtered to obtain 4.38 g of compound 2.

[0512] Synthesis of compound 3

[0513] In a 100 ml autoclave, 4.38 g of compound 2 and 1.31 g of palladium hydroxide on carbon were mixed, and 1,4-dioxane was added and dispersed evenly. After hydrogen replacement three times, the reaction was maintained at room temperature overnight. After the reaction was completed, the mother liquor was collected by filtration using a diatomaceous earth pad and dried for later use.

[0514] Synthesis of compound 4

[0515] 200 mg of compound SM2, 249.3 mg of compound 3, 472.5 mg of cesium carbonate, and 23 mg of PEPPSI-Pd were dispersed in 5 ml of 1,4-dioxane and heated to 100°C under nitrogen protection for overnight reaction. After the reaction was completed under TLC monitoring, the sample was directly mixed and dried by spin drying and passed through a column to obtain 50 mg of compound 4.

[0516] Synthesis of compound INT-12

[0517] 240 mg of compound 4 was dissolved in 3 ml of dichloromethane, and a solution of hydrogen chloride 1,4-dioxane was added dropwise and reacted at room temperature for 3 hours. LCMS confirmed that the reaction was complete, and the solvent was removed by rotary evaporation to obtain crude compound INT-12.

[0518] Synthesis of intermediate compound INT-13

[0519] Synthesis of compound 2

[0520] 500 mg of SM1, 558 mg of boc-piperazine, and 552 mg of potassium carbonate were added to a 100 ml single-necked bottle and dissolved in 10 ml of DMAC. The mixture was heated at 90°C and reacted overnight. After TLC showed that the reaction was complete, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate phase was dried, filtered, and then spin-dried and passed through a column to obtain 760 mg of compound 2.

[0521] Synthesis of compound 3

[0522] In a 100 ml single-necked bottle, 200 mg of compound 2, 56 mg of Pd(dppf)Cl2, 0.7 ml of triethylamine, 4 ml of DMF, and 4 ml of methanol were added and mixed. The mixture was ventilated three times with a carbon monoxide balloon, sealed with a balloon, and reacted at 85°C overnight. After TLC detection, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, and filtered to obtain 150 mg of a yellow oily compound 3. LC-MS [M+1]: 418

[0523] Synthesis of intermediate INT-13

[0524] In a 100ml single-necked flask, 150mg of compound 3, 10mg of palladium-carbon, and 3ml of methanol were added and mixed. The mixture was allowed to react at 35°C overnight. After the reaction, the mixture was filtered through a celite pad and the mother liquor was collected and dried to obtain the crude compound INT-13.

[0525] Synthesis of intermediate compound INT-14

[0526] The synthetic route is as follows:

[0527] 1. Synthesis of Compound 2

[0528] To a 500ml three-necked flask, add 10g of magnesium turnings and two iodine grains. Under nitrogen protection, dissolve the mixture in 150ml of tetrahydrofuran. Initiate with 0.1ml of 1,4-dibromobutane. Cool the reaction mixture to 0°C. Slowly add 12ml of 1,4-dibromobutane in 40ml of tetrahydrofuran, maintaining the temperature below 30°C. After complete addition, allow the reaction to proceed at room temperature for 2-3 hours. Cool the solution to 0°C and slowly add 6.8ml of diethyl phosphite, maintaining the temperature below 20°C. After complete addition, allow the reaction to proceed at room temperature. After TLC indicates the reaction is complete, cool the reaction mixture to 0°C and slowly add potassium carbonate solution (30g K2CO3 and 50g H2O), maintaining the temperature below 10°C, to quench the reaction. A large amount of solid precipitates. Filter the filtrate with suction, spin dry, and column column to yield 1.1g of compound 2, a colorless, transparent liquid. LC-MS [M+1]: 105.

[0529] 2. Synthesis of Compound 3

[0530] To a 100ml single-necked flask, add 1.1g of compound 2, 1.1g of iodoaniline, 1.6g of potassium phosphate, 152mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 59mg of palladium acetate. Dissolve the mixture in 24ml of 1,4-dioxane, then heat under nitrogen and react overnight at 80°C. After TLC analysis, the reaction mixture was cooled to room temperature, filtered, and the filtrate was dried by rotary evaporation. The mixture was then purified by column chromatography to yield 611mg of compound 3 as a brown oil. LC-MS [M+1]: 196.

[0531] 3. Synthesis of Intermediate INT-14

[0532] To a 100ml single-necked flask, 300mg of compound 3, 649mg of 2,4-dichloro-5-bromopyrimidine, and 1.5ml of N,N-diisopropylethylamine were added and dissolved in 6ml of isopropanol. The mixture was heated at 100°C under nitrogen atmosphere. After completion of the reaction, the intermediate INT-14 was purified by column chromatography to yield 309mg. LC-MS [M+1]: 388.

[0533] Synthesis of intermediate compound INT-15

[0534] The synthetic route is as follows:

[0535] 1. Synthesis of Compound 2

[0536] In a 100 mL three-necked flask, 2 g of SM1, 2.2 g of pinacol diboronate, 2.4 g of pd(dppf)Cl2, and 1.7 g of potassium acetate were dissolved in 30 mL of 1,4-dioxane. Under nitrogen, the temperature was raised to 85°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 2 g of compound 2. LC-MS [M+1]: 389.

[0537] 2. Synthesis of Compound 3

[0538] In a 250 mL three-necked flask, 2 g of compound 2, 2 g of SM2, 1.5 g of sodium carbonate, and 376 mg of pd(dppf)Cl2 were dissolved in 40 mL of 1,4-dioxane and 10 mL of H2O. Under N2 protection, the temperature was raised to 55°C and the reaction was allowed to proceed for 2 h. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was added with water and extracted with dichloromethane. The organic phase was washed once with saturated NaCl and dried. The sample was then spin-dried and purified by column chromatography to yield 1.8 g of compound 3. LC-MS [M+1]: 480.

[0539] 3. Synthesis of Compound 4

[0540] In a 100 mL single-necked flask, 1.8 g of compound 3 was dissolved in 18 mL of ethyl acetate. 1,4-dioxane hydrochloride was added and the mixture was allowed to react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was filtered to obtain 1 g of a filter cake, which was compound 4. LC-MS [M+1]: 380.

[0541] 4. Synthesis of Compound 5

[0542] In a 100-mL three-necked flask, 1 g of compound 4 was dissolved in 10 mL of DMF. Under nitrogen, 2 mL of N,N-diisopropylethylamine was added. After stirring for 10 min in an ice bath, 0.4 mL of tert-butyl bromoacetate was added. The reaction was allowed to react overnight at room temperature. Completion of the reaction was monitored by TLC. Water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by column chromatography to yield 1.5 g of compound 5. LC-MS [M+1]: 494.

[0543] 5. Synthesis of Compound 6

[0544] In a 100 mL reactor, 1.5 g of compound 5 and 228 mg of palladium on carbon were dissolved in 30 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 200 mg of compound 6. LC-MS [M+1]: 496.

[0545] 6. Synthesis of Intermediate INT-15

[0546] To a 100 mL reaction tube, add 200 g of compound 6, dissolve in 1 mL of dichloromethane, add 0.2 mL of trifluoroacetic acid, and react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was concentrated to remove the solvent, yielding 283 mg of intermediate INT-15. LC-MS [M+1]: 440.

[0547] Synthesis of intermediate compound INT-16

[0548] The synthetic route is as follows:

[0549] 1. Synthesis of Compound 2

[0550] In a 100 mL three-necked flask, 1 g of SM1 was dissolved in 20 mL of DMF. Under nitrogen, 260 mg of sodium hydride and 810 mg of 2-iodopropane were added under an ice bath. The reaction was allowed to react at room temperature for 1 h. TLC monitored the reaction until completion. The reaction solution was quenched with saturated ammonium chloride, extracted with water, and extracted with EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 776 mg of compound 2. LC-MS [M+1]: 274.

[0551] 2. Synthesis of Compound 3

[0552] In a 250 mL three-necked flask, 776 mg of compound 2, 0.3 mL of acrylic acid, and 92 mg of tetrabutylammonium bromide were dissolved in 8 mL of 2M hydrochloric acid. Under a nitrogen atmosphere, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and quenched with saturated sodium carbonate in an ice bath to a pH of 9. The pH was then adjusted to 3-4 with acetic acid. A large amount of white solid precipitated. After thorough stirring, the solution was filtered and the filter cake dried to yield 1.2 g of compound 3. LC-MS [M+1]: 346.

[0553] 3. Synthesis of Compound 4

[0554] In a 100 mL single-necked flask, 1.2 g of compound 3 was dissolved in 12 mL of acetic acid. 453 mg of sodium cyanate was added and the mixture was heated at 60°C for 14 h. 12 mL of 2M hydrochloric acid was added and the reaction continued at 60°C for 3 h. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and quenched with saturated sodium carbonate solution. Water was added and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to yield 330 mg of compound 4. LC-MS [M+1]: 369.1.

[0555] 4. Synthesis of Compound 5

[0556] In a 100 mL three-necked flask, 330 mg of compound 4, 340 mg of pinacol diboronate, 65 mg of pd(dppf)Cl2, and 262 mg of potassium acetate were dissolved in 7 mL of 1,4-dioxane. Under nitrogen, the temperature was raised to 85°C and the reaction was allowed to proceed overnight. TLC was used to monitor the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was then dried and the sample was purified by column chromatography to yield 434 mg of compound 5. LC-MS [M+1]: 417.

[0557] 5. Synthesis of Compound 6

[0558] In a 50-ml single-necked bottle, 434 mg of compound 5, 421 mg of SM2, 316 mg of sodium carbonate, and 76 mg of pd(dppf)Cl2 were dissolved in 4 mL of 1,4-dioxane and 2 mL of H2O. Under N2 protection, the temperature was raised to 55°C and the reaction was allowed to proceed for 2 h. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was dried, spin-dried, and the sample was purified by column chromatography to yield 265 mg of compound 6. LC-MS [M+1]: 508.

[0559] 6. Synthesis of Compound 7

[0560] In a 50 mL single-necked flask, 265 mg of compound 6 was dissolved in 3 mL of ethyl acetate. 2 mL of 1,4-dioxane hydrochloride was added and the mixture was allowed to react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction mixture was filtered to obtain 142 mg of a filter cake, which was compound 7. LC-MS [M+1]: 408.

[0561] 7. Synthesis of Compound 8

[0562] In a 50 mL single-necked flask, 142 mg of compound 7 was dissolved in 3 mL of DMF. Under nitrogen, 0.28 mL of N,N-diisopropylethylamine was added. After stirring for 10 minutes on ice, 0.06 mL of tert-butyl bromoacetate was added. The mixture was allowed to react overnight at room temperature. Completion of the reaction was monitored by TLC. The reaction solution was then added with water and extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography to yield 174 mg of compound 8. LC-MS [M+1]: 522.4.

[0563] 8. Synthesis of Compound 9

[0564] In a 50 mL single-necked flask, 174 mg of compound 8 and 17 mg of palladium on carbon were dissolved in 4 mL of methanol and 4 mL of ethyl acetate. The mixture was reacted at room temperature overnight under a H₂ atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography afforded 142 mg of compound 9. LC-MS [M+1]: 524.

[0565] 9. Synthesis of Intermediate INT-16

[0566] To a 10 mL reaction tube, add 142 mg of compound 9, dissolve in 2 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was concentrated to remove the solvent, yielding 265 mg of intermediate INT-16. LC-MS [M+1]: 468.2.

[0567] Synthesis of intermediate INT-17

[0568] The synthetic route is as follows:

[0569] 1. Synthesis of Compound 2

[0570] In a 50ml single-necked flask, 300mg of compound 1 (1.0 equivalent), 272mg of SM2 (1.0 equivalent), 280mg of sodium carbonate (1.5 equivalent), 6ml of 1,4-dioxane, and 1.5ml of water were mixed thoroughly under nitrogen. 63mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 equivalent) was added, the atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C. The reaction was allowed to react overnight. TLC monitored the reaction until completion, and the mixture was filtered through a pad of Celite. The mother liquor was collected and the solvent removed by rotary evaporation. 30ml of water was added, and the mixture was extracted three times with 15ml of ethyl acetate. The combined organic phases were mixed and passed through a column chromatography column to yield 345mg of compound 2.

[0571] 2. Synthesis of compound 3

[0572] In a 50ml single-necked flask, 345mg of compound 2 and 34.5mg of Pd / C were added to 3.4ml of MeOH. The atmosphere was replaced with hydrogen three times and the mixture was allowed to react at room temperature under a hydrogen balloon for 6 hours. After completion of the reaction, the reaction mixture was filtered to remove the palladium on carbon. The filtrate was then rotary evaporated to remove the solvent, yielding 345mg of compound 3. LC-MS [M+1]: 446.

[0573] 3. Synthesis of compound 4

[0574] In a 50 ml single-necked flask, add 345 mg of compound 3 and 2 ml of the tetradioxane hydrochloride solution to 3 ml of THF. React at room temperature for 6 h. After the reaction is complete, evaporate to dryness and use in subsequent reactions. LC-MS [M+1]: 346.

[0575] 4. Synthesis of Compound 5

[0576] In a 100-mL three-necked flask, 690 mg of compound 4 was dissolved in 7 mL of DMF. Under nitrogen, 3.5 mL of N,N-diisopropylethylamine was added. After stirring for 10 minutes on ice, 470 mg of tert-butyl bromoacetate was added. The mixture was allowed to react overnight at room temperature. Completion of the reaction was monitored by TLC. Water was added to the reaction solution, which was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and then spin-dried. The mixture was purified by column chromatography to yield 690 mg of compound 5. LC-MS [M+1]: 460.

[0577] 5. Synthesis of intermediate INT-17

[0578] To a 100 mL reaction tube, 363 mg of compound 6 was added and dissolved in 1 mL of dichloromethane. 0.2 mL of trifluoroacetic acid was added and the mixture was allowed to react at room temperature overnight. TLC indicated the disappearance of the starting material. The reaction solution was concentrated to remove the solvent, yielding 318 mg of intermediate INT-17. LC-MS [M+1]: 404.

[0579] Synthesis of intermediate INT-18

[0580] Synthesis of compound 2

[0581] In a 250 mL three-necked flask, 2.0 g of SM1 and 1.06 g of dimethylphosphine were dissolved in 20 mL of NN-dimethylformamide. Under N2 protection, 2.9 g of potassium phosphate, 204 mg of palladium acetate, and 525 mg of Xnatphos were added. After nitrogen replacement three times, the reaction was carried out at 115 ° C overnight. The reaction was monitored by TLC until completion. The reaction solution was added with water and extracted with EA. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and subjected to column chromatography to obtain 350 mg of compound 2.

[0582] Synthesis of intermediate INT-18

[0583] In a 100-ml single-necked flask, 300 mg of compound 2, 649 mg of trichloropyrimidine, and 1.5 ml of N,N-diisopropylethylamine were added and dissolved in 6 ml of isopropanol. The mixture was heated at 100°C under nitrogen atmosphere. After completion of the reaction, the intermediate INT-18 was purified by column chromatography to yield 309 mg of intermediate INT-18. LC-MS [M+1]: 318.

[0584] Synthesis of intermediate compound INT-19

[0585] The synthetic route is as follows:

[0586] 1. Synthesis of Compound 2

[0587] In a 500 mL three-necked flask, 29 g of SM1 was dissolved in 290 mL of anhydrous ethanol. Under nitrogen, 35 mL of methylhydrazine was added and the reaction was heated at 80°C. The reaction was monitored for completion by TLC. The reaction solution was cooled to room temperature and stirred thoroughly in an ice bath. A large amount of white solid precipitated. Filtering afforded a filter cake, which was dried to yield 15.7 g of the product. Column chromatography of the filtrate afforded 9 g of the product, yielding a total of 24.7 g of compound 2 as a pale yellow solid. LC-MS [M+1]: 246.1.

[0588] 2. Synthesis of Compound 3

[0589] In a 500 mL three-necked flask, 24.7 g of compound 2, 10.4 mL of acrylic acid, and 3.2 g of tetrabutylammonium bromide were dissolved in 250 mL of 2M hydrochloric acid solution. The temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and quenched with saturated sodium carbonate in an ice bath to a pH of 9. The pH was then adjusted to 3-4 with acetic acid. A large amount of white solid precipitated. After thorough stirring, the mixture was filtered and the filter cake dried to yield 26 g of compound 3 as a yellow solid. LC-MS [M+1]: 316.1.

[0590] 3. Synthesis of Intermediate INT-19

[0591] In a 1L single-necked flask, 26g of compound 3 was dissolved in 260mL of acetic acid. 10.6g of sodium cyanate was added and the mixture was heated at 60°C for 14h. 260ml of 2M hydrochloric acid was added and the reaction continued at 60°C for 3h. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and stirred thoroughly in an ice bath. A large amount of white solid precipitated. Filter and dry the filter cake to yield 10.7g of INT-19 as a yellow solid. LC-MS [M+1]: 342.

[0592] Example 2-1: Synthesis of Compound TB-006

[0593] The synthetic route is as follows:

[0594] 1. Synthesis of Compound 2

[0595] To a 10ml reaction tube, 100mg of intermediate INT-14, 97mg of intermediate INT-11, and 46mg of zinc chloride were added in sequence. The mixture was dissolved in 2ml of isopropanol and heated at 105°C overnight under nitrogen atmosphere. After TLC analysis of the reaction, the reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried, concentrated, and purified by column chromatography to yield 73mg of compound 2. LC-MS [M+1]: 726.

[0596] 2. Synthesis of Compound 3

[0597] To a 10 ml reaction tube, add 73 mg of compound 2 and 1 ml of trifluoroacetic acid, dissolve in 2 ml of dichloromethane, and react at room temperature for 0.5 h. After TLC analysis of the reaction, the reaction solution was concentrated to remove the solvent, yielding 58 mg of compound 3. LC-MS [M+1]: 627.

[0598] 3. Synthesis of Compound TB-006

[0599] To a 10ml reaction tube, 116mg of intermediate INT-15 was added, dissolved in 2ml of DMF, and then 0.15ml of DIPEA was added. Under nitrogen, the mixture was stirred in an ice bath for 10 minutes. 58mg of compound 3 and 45mg of HATU were then added, and the mixture was allowed to react at room temperature overnight. After TLC analysis of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to yield 17mg of compound TB-006. LC-MS [M+1]: 1047 HPLC: 96%

[0600] 1 H NMR (400MHz, DMSO) δ10.58(s,2H),8.30(s,1H),8.14(s,1H),8.03(s,1H),7.70(d,J=5.2Hz,1H),7.45(dd, J=18.0,9.1Hz,2H),7.35(s,1H),7.14(s,2H),6.15(s,1H),4.03(s,4H),3.92(t,J=6.5Hz,3H),3.74(s,3H) ,3.68(s,5H),3.02(s,2H),2.81–2.73(m,3H),2.68(s,1H),2.45–2.35(m,3H),2.34(s,1H),2.08(s,2H),1 .99(s,5H),1.84(s,5H),1.74(s,2H),1.28(d,J=13.0Hz,1H),1.18(t,J=7.1Hz,1H),1.02(t,J=7.3Hz,3H).

[0601] Referring to the synthesis method of the intermediate compound INT-14 and the synthesis method of the compound TB-006, the following compounds were synthesized respectively:

[0602] The following chiral compounds were obtained by high pressure preparative chromatography:

[0603] Example 2-2: Synthesis of Compound TB-008

[0604] The synthetic route is as follows:

[0605] In a 50 mL round-bottom flask, 50 mg of compound 3 and 75 mg of INT-17 were dissolved in 3 mL of DMF. 0.14 mL of DIPEA and 40 mg of HATU were added. After three N2 ventilation cycles, the reaction was allowed to react at room temperature for 3 h. TLC confirmed the reaction was complete. The reaction solution was extracted with ethyl acetate and water, then dried under reduced pressure and subjected to column chromatography to yield 19 mg of compound TB-008. LC-MS [M+1]: 1012.5. NMR(400MHz,DMSO-d6)δ10.62(s,1H),10.57(s,1H),8.31(s,1H),8.14(s,1H),8.04(s,1H),7.57( d,J=5.9Hz,1H),7.46(dd,J=13.5,7.7Hz,1H),7.38(d,J=10.9Hz,2H),7.14(s,2H),6.14(s,1H),4 .01(s,3H),3.90(t,J=6.6Hz,2H),3.71(d,J=21.6Hz,7H),3.22(s,2H),2.99(d,J=10.8Hz,3H),2. 85(s,2H),2.75(t,J=6.5Hz,2H),2.40(d,J=7.5Hz,2H),2.26–1.64(m,20H),1.02(t,J=7.4Hz,3H).

[0606] Referring to the synthesis method of compound TB-008, the following compounds were synthesized:

[0607] Example 2-3: Synthesis of Compound TB-018

[0608] The synthetic route is as follows:

[0609] Synthesis of compound TB-018

[0610] 78 mg of intermediate INT-16 was added to a 10 ml reaction tube, dissolved in 1 ml of DMF, and then 0.13 ml of DIPEA was added. Under nitrogen protection, the mixture was stirred in an ice bath for 10 minutes. 50 mg of compound 3 and 39 mg of HATU were then added, and the mixture was allowed to react at room temperature overnight. After TLC analysis of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to yield 22 mg of compound TB-018. LC-MS [M+1]: 1077 HPLC: 99.14%

[0611] 1H NMR (400MHz, DMSO) δ10.60(d,J=21.0Hz,2H),8.32(s,1H),8.10(d,J=35.3Hz,2H),7.75(s ,1H),7.52–7.28(m,3H),7.14(s,2H),6.15(s,1H),5.08(s,1H),3.93(s,2H),3.71(d,J=2 2.7Hz,7H),3.51(s,5H),3.02(s,1H),2.72(d,J=33.1Hz,3H),2.42(s,2H),2.09(s,2H),1 .98(s,4H),1.85(s,5H),1.74(s,2H),1.44(s,5H),1.24(s,5H),1.03(s,3H),0.86(s,1H).

[0612] Referring to the synthesis method of compound TB-018, the following compounds were synthesized:

[0613] Example 2-4:

[0614] Synthesis of intermediate compound M2

[0615] 1. Synthesis of Compound 2

[0616] In a 250 mL three-necked flask, 8.4 g of SM1, 9 g of potassium vinyl trifluoroborate, 2.4 g of Pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 5.3 g of compound 2. LC-MS [M+1]: 198.

[0617] 2. Synthesis of compound 3

[0618] In a 250 mL three-necked flask, 0.3 g of compound 2, 609 mg of 4-tert-butoxycarbonylaminopiperidine, and 631 mg of potassium carbonate were dissolved in 10 mL of DMAC. The mixture was heated to 100°C under N2 protection and allowed to react overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with water and EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 400 mg of compound 3. LC-MS [M+1]: 378.

[0619] 3. Synthesis of compound 4

[0620] In a 100 mL single-necked flask, 400 mg of compound 3 and 20 mg of palladium on carbon were dissolved in 10 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 340 mg of compound 4. LC-MS [M+1]: 350.

[0621] 4. Synthesis of intermediate M2

[0622] In a 100-ml reaction tube, 100 mg of compound 4, 90 mg of intermediate M1, and 70 mg of p-toluenesulfonic acid monohydrate were dissolved in 2 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The reaction was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography to obtain 70 mg of intermediate M2. LC-MS [M+1]: 529.

[0623] Synthesis of compound TC-085

[0624] In a 100 mL reaction tube, 70 mg of compound M2 and 138 mg of intermediate compound INTC-15 were dissolved in 1 mL of NN-dimethylformamide. The temperature was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath under nitrogen for 1 hour. The temperature was naturally raised to room temperature and the reaction was allowed to proceed overnight. The reaction was determined to be complete by TLC. The mixture was extracted with dichloromethane and water. The organic phase was dried and purified by column chromatography to obtain 18 mg of TC-085. LC-MS [M+1]: 950.7.

[0625] 1H NMR(400MHz,DMSOd6)δ11.16(s,1H),10.61(s,1H),8.43(s,1H),8.16(s,1H),8.11(s,1H),7.74(d,J=6.4Hz,2H ),7.55(dd,J=14.1,7.7Hz,1H),7.44(d,J=9.5Hz,2H),7.32(s,1H),7.11(t,J=7.2Hz,1H),6.82(s,1H),4.02(s, 3H),3.92(t,J=6.8Hz,2H),3.81(s,1H),3.72(s,3H),3.56(s,1H),3.18(s,2H),3.07–2.92(m,3H),2.88–2.71(m ,5H),2.56(t,J=7.6Hz,4H),1.88(s,3H),1.77(d,J=13.5Hz,5H),1.65(d,J=11.2Hz,2H),1.07(t,J=7.5Hz,3H).

[0626] Referring to the synthesis method of intermediate compound M2 and the synthesis method of compound TC-085, the following compounds were synthesized respectively:

[0627] The following chiral compounds were obtained by high pressure preparative chromatography:

[0628] Example 2-5: Synthesis of Compound TC-113

[0629] Synthesis of compound TC-113

[0630] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-113 was synthesized: 33 mg, LC-MS [M+1]: 937.5 1H NMR (400 MHz, DMSO-d6) δ10.60 (s, 1H), 8.47 (s, 1H), 8.30 (s, 1H), 7.93–7.83 (m, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.45 (td, J = 11.5, 10.6, 5.5 Hz, 3H), 7.28 (s, 1H), 6.72 (s, 1H), 4.01 (s, 3H), 3.9 1(t,J=6.7Hz,2H),3.69(d,J=27.8Hz,7H),3.56(d,J=11.7Hz,2H),3.45(s,3H),3.04(d,J=10.8Hz,1H), 2.77(dd,J=19.0,12.1Hz,8H),2.39(s,4H),1.85(d,J=12.1Hz,1H),1.64(d,J=13.6Hz,6H),0.95(s,3H).

[0631] Example 2-6: Synthesis of Compound TC-117

[0632] Synthesis of compound TC-117

[0633] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-117 was synthesized. LC-MS [M+1]: 916.5 1H NMR (400 MHz, DMSO-d6) δ11.17 (s, 1H), 10.57 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.59–7.51 (m, 1H), 7.47 (s, 1H), 7.38–7.29 (m, 2H), 7.18–7.08 (m, 2H), 6.82 (s, 1H), 5.01 (s, 1H), 3.95 (s, 3H), 3.89 (t, J = 6.7 Hz, 2H), 3.71 (s, 3H), 3.60–3.48 (m, 1H), 3.1 9(d,J=11.0Hz,3H),3.08(t,J=11.0Hz,3H),2.85(d,J=13.2Hz,4H),2.74(t,J=6.7Hz,2H),2.60(dd,J=15. 8,8.3Hz,5H),2.00(q,J=7.8Hz,2H),1.84(d,J=11.2Hz,2H),1.77(d,J=13.6Hz,8H),1.08(t,J=7.5Hz,3H).

[0634] Referring to the synthesis method of compound TB-006 in Example 2-1, the following compounds were synthesized:

[0635] Example 2-7: Synthesis of Compound TC-123

[0636] Synthesis of intermediate compound M1

[0637] Synthesis of compound 2

[0638] 500 mg of SM1, 558 mg of boc-piperazine, and 552 mg of potassium carbonate were added to a 100 ml single-necked bottle and dissolved in 10 ml of DMAC. The mixture was heated at 90°C and reacted overnight. After TLC showed that the reaction was complete, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate phase was dried, filtered, and then spin-dried and passed through a column to obtain 760 mg of compound 2.

[0639] Synthesis of compound 3

[0640] In a 100 ml single-necked bottle, 200 mg of compound 2, 56 mg of Pd(dppf)Cl2, 0.7 ml of triethylamine, 4 ml of DMF, and 4 ml of methanol were added and mixed. The mixture was ventilated three times with a carbon monoxide balloon, sealed with a balloon, and reacted at 85°C overnight. After TLC detection, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, and filtered to obtain 150 mg of a yellow oily compound 3. LC-MS [M+1]: 418

[0641] Synthesis of compound 4

[0642] In a 100 ml single-necked bottle, 150 mg of compound 3, 10 mg of palladium carbon, and 3 ml of methanol were added and mixed. The mixture was allowed to react at 35°C overnight. After the reaction, the mixture was filtered through a celite pad and the mother liquor was collected and dried to obtain crude compound 4.

[0643] Synthesis of intermediate M1

[0644] In a 100 ml single-necked bottle, 112 mg of the intermediate pyrimidine, 130 mg of compound 4, 87 mg of p-toluenesulfonic acid monohydrate, and 4 ml of isopropanol were heated to 90°C and reacted overnight. After the reaction, 60 mg of the intermediate M1 was obtained by column chromatography purification.

[0645] Synthesis of compound TC-123

[0646] Compound TC-123 was synthesized by referring to the synthesis method of compound TB-006 in Example 2-1.

[0647] LC-MS[M+1]: 966.6 1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.60(s,1H),8.40(s,2H),8.11(s,1H),7.94(s,1H),7.71 (d,J=5.6Hz,1H),7.49–7.37(m,2H),7.23(d,J=9.4Hz,1H),7.01(d,J=7.6Hz,1H),6.75(s,1H),3 .97(s,3H),3.91(t,J=6.7Hz,2H),3.85(s,3H),3.73(s,6H),3.59(s,2H),3.15–2.94(m,6H),2.8 4–2.66(m,4H),2.39(d,J=12.5Hz,2H),2.00(d,J=8.2Hz,1H),1.85(s,1H),1.76(d,J=13.4Hz,6H)

[0648] Referring to the synthesis method of intermediate compound M1 and the synthesis method of compound TC-123, the following compounds were synthesized respectively:

[0649] Example 2-8: Synthesis of Compound TC-135

[0650] Synthesis of compound TC-135

[0651] 278 mg of intermediate INTC-15 was added to a 10 ml reaction tube, dissolved in 2 ml of DMF, and then 0.4 ml of DIPEA was added. Under nitrogen, the mixture was stirred in an ice bath for 10 minutes. 115 mg of intermediate M1 and 107 mg of HATU were then added, and the mixture was allowed to react at room temperature overnight. After TLC analysis of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to yield 10 mg of compound TC-135. LC-MS [M+1]: 949.8 HPLC: 95.49%

[0652] 1 H NMR (400MHz, DMSO) δ11.22(s,1H),10.59(s,1H),8.50(s,2H),8.09(s,1H),7.68(d,J=4.6Hz,1H),7.48(dd,J=14.2,8.3Hz,1H),7.44(d,J=10.4Hz,1H ),7.27(s,1H),7.10–7.00(m,2H),4.42(s,2H),4.12(dd,J=10.5,5.2Hz,1 H),3.98(s,2H),3.92(t,J=6.8Hz,2H),3.57(t,J=6.4Hz,1H),3.50(s,1H), 3.46(s,1H),3.29–3.26(m,1H),3.25(s,1H),3.17(d,J=5.2Hz,2H),3.06( d,J=9.7Hz,2H),2.93(s,3H),2.82–2.69(m,3H),2.62(dd,J=14.8,7.5Hz,2 H),2.53(s,1H),2.43–2.31(m,2H),2.12–1.94(m,1H),1.88(s,1H),1.76(d ,J=13.5Hz,5H),1.24(s,1H),1.12(t,J=7.4Hz,3H),0.85(d,J=6.8Hz,1H).

[0653] Example 2-9: Synthesis of Compound TC-144

[0654] Synthesis of compound TC-144

[0655] Compound TC-144 was synthesized by referring to the synthesis method of compound TB-006 in Example 2-1.

[0656] LC-MS[M+1]: 957.7 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),10.60(s,1H),8.31(d,J=8.2Hz,1H),8.19(s,1H),8.14(s,1H),7. 61–7.43(m,4H),7.36(s,1H),7.14(t,J=7.6Hz,1H),6.83(s,1H),5.16(s,2H),4.03(d,J=6.0Hz,4H),3. 93(t,J=6.6Hz,2H),3.77(s,9H),2.88(d,J=25.6Hz,5H),2.77(t,J=6.7Hz,2H),2.58(d,J=7.4Hz,3H),2 .11(d,J=10.1Hz,6H),1.99(s,2H),1.76(d,J=13.5Hz,6H),1.17(t,J=7.1Hz,2H),1.06(t,J=7.4Hz,3H).

[0657] Referring to the synthesis method of compound TC-144 in Example 2-9, the following compounds were synthesized:

[0658] Example 2-10: Synthesis of Compound TC-150

[0659] Synthesis of compound TC-150

[0660] Compound TC-150 was synthesized by referring to the synthesis method of compound TB-006 in Example 2-1.

[0661] LC-MS[M+1]: 1042.4 1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.72(s,1H),8.31(s,1H),8.19(s,1H),8.15(s ,1H),7.77–7.64(m,3H),7.64–7.44(m,5H),7.43–7.26(m,2H),7.08(s,1H),6.78(s,1 H),4.05(t,J=6.7Hz,2H),3.69(d,J=17.4Hz,9H),3.03(d,J=10.7Hz,2H),2.94–2.70( m,8H),2.31–2.10(m,3H),1.93(s,2H),1.74(d,J=13.5Hz,6H),1.06(t,J=7.4Hz,3H).

[0662] Example 2-11: Synthesis of Compound TC-215

[0663] Compound TC-150 was synthesized by referring to the synthesis method of compound TB-006 in Example 2-1.

[0664] LC-MS[M+1]: 918.6 1HNMR (400MHz, DMSO) δ11.17(s,1H),10.58(s,1H),8.42(s,1H),8.15(d,J=31.0Hz,2H),7.54(dd,J=30.8,20. 5Hz,4H),7.32(s,1H),7.08(s,2H),6.81(s,1H),3.96(s,2H),3.92(s,2H),3.74(s,5H),3.60(s,2H),3.43(d,J =7.5Hz,2H),3.23(s,2H),3.03(s,1H),2.91(s,2H),2.79(d,J=27.0Hz,3H),2.65(d,J=7.7Hz,1H),2.61(d,J=6 .7Hz,2H),2.27(d,J=11.1Hz,1H),1.99(s,1H),1.89(s,1H),1.76(d,J=13.3Hz,5H),1.23(s,3H),1.09(s,3H).

[0665] Example 2-12: Synthesis of Compound TC-099

[0666] Synthesis of intermediate 3

[0667] The synthetic route is as follows:

[0668] 1. Synthesis of Compound 2

[0669] To a 50 mL three-necked flask, weigh 600 mg of 1 and dissolve it in 6 mL of DMF. Then, add 188 mg of Al and 469 mg of DIPEA. After purging with N2 three times, react at 90°C overnight. TLC monitoring revealed the formation of new spots. The reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by column chromatography to yield 448 mg of compound 2.

[0670] 2. Synthesis of Intermediate 3

[0671] In a 50 mL single-necked flask, 448 mg of compound 2 and 252 mg of DIPEA were dissolved in 5 mL of DCM. 206 mg of A2 was dissolved in 2 mL of DCM and slowly added dropwise to the reaction mixture. After three N2 ventilations, the mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC until the reduction of compound 2 ceased. The reaction mixture was then directly dried under reduced pressure and subjected to column chromatography to yield 286 mg of intermediate 3.

[0672] Synthesis of compound TC-099

[0673] The synthetic route is as follows:

[0674] In a 50 ml round-bottom flask, 186 mg of compound M3 and 119 mg of raw material amine (compound 3 in INT-17) were dissolved in 3 mL of acetonitrile, and then 82 mg of KI and 159 mg of DIPEA were added. After N2 ventilation three times, the reaction was carried out at 75 ° C for 3 h. The reaction was detected to be complete by TLC. The reaction solution was dried under reduced pressure and the sample was mixed and subjected to column chromatography to obtain 190 mg of compound TC-099.

[0675] LC-MS[M+1]: 922.7.1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.61(s,1H),8.44(s,1H),8.17(s,1H),8.11(s,1H),7.75(d, J=5.5Hz,1H),7.55(dd,J=14.1,7.7Hz,1H),7.42(d,J=8.7Hz,2H),7.32(s,1H),7.12(d,J=8.2Hz,1H ),6.81(s,1H),4.03(s,3H),3.92(t,J=6.6Hz,2H),3.77(s,3H),3.12(s,2H),2.86(d,J=5.6Hz,4H), 2.76(t,J=6.7Hz,3H),2.71–2.63(m,4H),2.37(s,3H),1.77(d,J=13.5Hz,7H),1.07(t,J=7.5Hz,3H)

[0676] Comparative Example 2-1: DZL-1

[0677] The synthesis method refers to Haisike WO2024083183A1

[0678] Comparative Example 2-2: DZL-2

[0679] The synthesis method refers to T-14 in Tongyuankang WO2023088385A1

[0680] Example 3-1: Synthesis of compound TD-001

[0681] Synthesis of intermediate compound M1

[0682] 1. Synthesis of Compound 2

[0683] In a 250 mL three-necked flask, 10 g of SM1, 10.7 g of vinyl boron trifluoride, 2.9 g of Pd(dppf)Cl2, and 8.2 g of potassium carbonate were dissolved in 50 mL of 1,4-dioxane and 10 mL of H2O. Under nitrogen, the temperature was raised to 100°C and the reaction was allowed to proceed overnight. TLC monitored the reaction until completion. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA, and the organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 14.4 g of compound 2. LC-MS [M+1]: 198.

[0684] 2. Synthesis of compound 3

[0685] In a 100-mL three-necked flask, 2.7 g of compound 2, 4.3 g of 1-Boc-piperazine, and 9.4 g of potassium carbonate were dissolved in 27 mL of DMAC. The mixture was heated to 100°C under N2 protection and allowed to react overnight. TLC indicated the disappearance of the starting material. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with water and EA. The organic phase was washed once with saturated NaCl and dried. The sample was then directly spin-dried and purified by column chromatography to yield 3.8 g of compound 3. LC-MS [M+1]: 364.

[0686] 3. Synthesis of compound 4

[0687] In a 100 mL reactor, 3.8 g of compound 3 and 1.5 g of palladium on carbon were dissolved in 35 mL of methanol. The mixture was reacted at room temperature overnight under a H2 atmosphere. TLC indicated the disappearance of the starting material. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly spin-dried and mixed. Column chromatography yielded 2.9 g of compound 4. LC-MS [M+1]: 336.

[0688] 4. Synthesis of intermediate M1

[0689] In a 100 ml reaction tube, 300 mg of compound 4, 265 mg of SM2, and 220 mg of p-toluenesulfonic acid monohydrate were dissolved in 3 mL of isopropanol. Under N2 protection, the temperature was raised to 90°C and the reaction was allowed to react overnight. TLC monitored the reaction until completion. The mixture was quenched with a small amount of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness. The mixture was purified by column chromatography to obtain 331 mg of intermediate M1. LC-MS [M+1]: 496.

[0690] Synthesis of intermediate compound M2

[0691] The synthetic route is as follows:

[0692] 1. Synthesis of compound 2a

[0693] In a 50ml three-necked flask, 220mg of compound 1a (1.0 equivalent), 67mg of bromoethanol (1.2 equivalents), 172mg of DIPEA (3.0 equivalents), and 5ml of DMF were mixed and allowed to react at 90°C overnight under reflux. Completion of the reaction was monitored by TLC (DCM:MEOH = 10:1). The reaction solution was cooled to room temperature and diluted with 5ml of EA. Extraction was performed three times with 15ml of ethyl acetate. The combined organic phases were passed through a column chromatography column to yield 140mg of compound 2a.

[0694] 2. Synthesis of Compound M2

[0695] In a 50 ml single-necked flask, 140 mg of compound 2a, 99 mg (2.0 eq) of TosCl, and 79 mg (3.0 eq) of triethylamine were dissolved in 2.8 ml of DCM. The mixture was stirred at room temperature and allowed to react for 16 h. The solvent was removed by rotary evaporation, and 60 mg of compound M2 was obtained by column chromatography.

[0696] Synthesis of intermediate M3

[0697] The synthetic route is as follows:

[0698] 1. Synthesis of compound 2b

[0699] In a 50ml single-necked flask, 300mg of compound 1b (1.0 equivalent), 272mg of SM2 (1.0 equivalent), 280mg of sodium carbonate (1.5 equivalent), 6ml of 1,4-dioxane, and 1.5ml of water were mixed thoroughly under nitrogen. 63mg of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.1 equivalent) was added, the atmosphere was purged with nitrogen three times, and the temperature was raised to 100°C. The reaction was allowed to react overnight. TLC monitored the reaction until completion, and the mixture was filtered through a pad of Celite. The mother liquor was collected and the solvent removed by rotary evaporation. 30ml of water was added, and the mixture was extracted three times with 15ml of ethyl acetate. The combined organic phases were mixed and passed through a column chromatography column to yield 345mg of compound 2b.

[0700] 2. Synthesis of compound 3b

[0701] In a 50ml single-necked flask, 345mg of compound 2b and 34.5mg of palladium on carbon were added to 3.4ml of MeOH. The atmosphere was replaced with hydrogen three times and the mixture was allowed to react at room temperature under a hydrogen balloon for 6h. After completion of the reaction, the reaction mixture was filtered to remove palladium on carbon. The filtrate was then rotary evaporated to remove the solvent, yielding 345mg of compound 3b. LC-MS [M+1]: 446.

[0702] 3. Synthesis of Compound M3

[0703] In a 50 ml single-necked flask, add 345 mg of compound 3b and 2 ml of the tetradioxane hydrochloride solution to 3 ml of THF. React at room temperature for 6 h. After the reaction is complete, evaporate to dryness and use in subsequent reactions. LC-MS [M+1]: 346.

[0704] Synthesis of compound TD-001

[0705] The synthetic route is as follows:

[0706] In a 50 mL round-bottom flask, 60 mg of compound M2 and 65 mg of M3 were dissolved in 1.2 mL of acetonitrile. 17.2 mg of KI and 33 mg of DIPEA were added. After three N2 ventilation cycles, the mixture was reacted at 75°C for 16 h. TLC confirmed the reaction was complete. The reaction solution was then vacuum-dried and the sample was then purified by column chromatography to yield 33 mg of compound M2.

[0707] LC-MS[M+1]: 867.41.

[0708] 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),10.58(s,1H),8.77(d,J=5.0Hz,1H),8.57( d,J=8.5Hz,1H),8.20(s,1H),8.14(s,1H),7.73(d,J=7.9Hz,1H),7.57(d,J=5.9Hz ,1H),7.48(s,1H),7.39(d,J=10.9Hz,1H),7.31(t,J=8.1Hz,1H),7.08(t,J=7.6H z,1H),6.81(s,1H),4.01(s,3H),3.91(t,J=6.7Hz,2H),3.77(s,3H),2.90(s,4H), 2.83–2.72(m,5H),2.58(q,J=7.6Hz,1H),1.90(s,4H),1.24(d,J=8.0Hz,4H),1.08(t,J=7.5Hz,3H).

[0709] Referring to the synthesis method of intermediate compound M2 and the synthesis method of compound TD-001, the following compounds were synthesized respectively:

[0710] Comparative Example 3-1: Synthesis of Compound C1

[0711] The synthetic route is as follows:

[0712] Compounds M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml of NN-dimethylformamide in a 50 ml round-bottom flask and cooled to 0°C in an ice-water bath. NN-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added with stirring. The mixture was reacted in an ice-water bath under nitrogen for 1 hour. The temperature was naturally raised to room temperature. The reaction was determined to be complete by TLC. The mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and purified by column chromatography to obtain 90 mg of reference compound C1. LC-MS [M+1]: 899.6.

[0713] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),10.64(s,1H),8.80(s,1H),8.70–8.54(m,1H),8.29(s,1H),8.21(s,1H),7. 76(d,J=7.8Hz,1H),7.71–7.52(m,3H),7.38(s,1H),7.13(q,J=8.5,7.6Hz,2H),6.88(s,1H),4.12–3.93(m,6H),3. 79(d,J=18.4Hz,5H),3.68(s,3H),3.53–3.51(m,1H),3.20(d,J=7.6Hz,2H),3.10(s,1H),2.98(s,2H),2.93–2.78 (m,8H),2.69(d,J=7.4Hz,1H),2.33(d,J=12.9Hz,1H),2.05(s,1H),1.94(d,J=13.0Hz,1H),1.16(t,J=7.6Hz,3H).

[0714] Test of compound's cell growth inhibitory activity

[0715] Test Example 1 Cell Anti-Proliferation Experiment

[0716] 1. Experimental materials and equipment:

[0717] H1975 has an EGFR:T790M / L858R double mutation, PC-9 has an EGFR exon 19 deletion, and HCC827 has an exon 19 deletion mutation. Baf3-19del-T790M-C797S (Baf3-DTC for short) is a stable Ba / F3 clone expressing exogenous EGFR gene bearing T790M, C797S and L858R triple amino acid mutations, purchased from Kangyuan Bochuang. Baf3-L858R-T790M-C797S (Baf3-LTC for short) is a stable Ba / F3 clone expressing exogenous EGFR gene bearing exon 19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Bochuang. A549 (wild-type EGFR) was purchased from Nanjing Kebai Biotechnology Co., Ltd., and A431 (wild-type EGFR) was purchased from Shanghai Xinyu Biotechnology Co., Ltd. CellCounting-Lite 2.0, Trypsin EDTA, 37°C CO2 incubator, cell counter, EnVision Serial No. 1050454.

[0718] 2. Experimental preparation:

[0719] 1. 96-well plate plating

[0720] A) Logarithmic phase cells were digested with Trypsin EDTA, the reaction was terminated by adding culture medium, and the cells were mixed by pipetting to prepare a cell suspension.

[0721] B) Use Vi-cell to determine the cell concentration and prepare a suspension of 15,000-25,000 cells per ml based on the experimental purpose and cell characteristics.

[0722] C) After the cell suspension is prepared, mix gently and add 100 μl to each well so that the cell density to be measured is 1500-2500 per well.

[0723] 2. Compound treatment

[0724] Compound dilution

[0725] A) Weigh approximately 2 mg of compound and calculate the required volume of DMSO according to the formula: compound mass (mg) * compound purity (%) / compound molecular weight * 1000

[0726] B) The inoculated cell culture plate is placed in an incubator and cultured for about 24 hours, and compounds with gradient concentrations are added.

[0727] C) Dilute 10 mM compound stock solution to 50 mM with culture medium, add 50 mM compound solution to the second column of the deep-well plate, and add 375 ml of culture medium containing 0.5% DMSO to the third to eleventh columns.

[0728] D) Serial dilution: Pipette 125 μl of solution from the second column and add it to the third column. Mix thoroughly. Then, pipette 125 μl of solution from the third column and add it to the fourth column. Repeat this process until the tenth column.

[0729] E) Using a multichannel pipette, pipette 25 μL of compound from the deep-well plate and add it to a 96-well plate. Repeat three times for each compound in the 96-well plate. Finally, a 1:4 concentration gradient is formed with a maximum concentration of 10,000 nM on the 96-well plate.

[0730] 3. Add CTG and read the reading

[0731] A) The 96-well plate was incubated in an incubator for 72 hours, and the effects of the compounds were observed under an inverted microscope.

[0732] B) Add 25 μl of CTG solution to each well, place on a shaker for 10 minutes, and read the OD value of each well.

[0733] 4. Data Analysis

[0734] The cell viability (%Cell Viability) was calculated using the following formula:

[0735] %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC)

[0736] Lum_HC: 0.1% DMSO control group cell readings

[0737] Lum_Sample: Cell readout with added compound

[0738] Lum_LC: Blank medium reading

[0739] The IC50 values ​​were obtained by curve fitting using GraphPad Prism 8 software.

[0740] As shown in Table 1, AA≤10nM; 10nM <A≤100nM;100nM<B<1000nM;C≥1000nM。

[0741] Table 1

[0742] As can be seen from Table 1, the compounds of the present invention have very good inhibitory effects on H1975 (human lung adenocarcinoma cells), BaF3-LTC and BaF3-DTC, and have a lesser inhibitory effect on cells containing exon 19 deletion. The inhibitory effect on wild-type EGFR is not obvious.

[0743] In addition, based on Table 1, the following conclusions are drawn:

[0744] 1) Comparison of TA-023 and TC-157 revealed that the spirocyclic structure in Ring B exhibited superior inhibitory activity against the L858 mutation compared to the piperazine ring and also improved inhibition of wild-type EGFR.

[0745] 2) Comparison of TC-225 with TA-023 shows that inhibition of mutant EGFR is reduced when the helical ring position is altered;

[0746] 3) Comparison of TC-213 and TC-215 with TC-157 revealed that adding fluorine atoms at specific positions can enhance the inhibitory effect on EGFR and reduce the inhibitory effect on wild-type EGFR;

[0747] 4) Comparison of TC-185 and TC-157 revealed that the use of a cyclic phosphine oxide structure instead of a dimethylphosphine structure enhanced the selectivity for wild-type EGFR.

[0748] 5) Comparison of TB-006 and DZL-1 (Control Example 2-1) shows that TB-006 has a better inhibitory effect on H1975, BaF3-LTC, and BaF3-DTC.

[0749] 6) Comparison of TA-023 with control example 2-2 shows that the new E3 and spirocyclic structure has better inhibitory activity against the L858 mutation than the original structure and is more selective for wild-type EGFR.

[0750] Experimental Example 2 EGFR PROTAC HTRF Experiment

[0751] 1. Instruments and reagents

[0752] Among them, Baf3-19del-T790M-C797S (abbreviated as Baf3-DTC) is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing T790M, C797S and L858R triple amino acid mutations, purchased from Kangyuan Botech. Baf3-L858R-T790M-C797S (abbreviated as Baf3-LTC) is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Botech.

[0753] 2. Experimental procedures

[0754] 1) Cell preparation:

[0755] 2) Reagent preparation:

[0756] Dilute Eu and d2 antibody 20-fold with detection buffer at a rate of 2 μl antibody per well. Then mix the two antibodies.

[0757] 3) Detection:

[0758] 3. Results and calculations

[0759] Open EnVision, find the HTRF program, set up the plate, and then read the plate.

[0760] Use GraphPad Prism to generate the fitting curve, DC50 and Dmax of the compound.

[0761] As shown in Table 2, for DC50, AA ≤ 10 nM; 10 nM < A ≤ 100 nM; 100 nM < B < 1000 nM; C ≥ 1000 nM; for Dmax, 70% ≤ A ≤ 100%; 50% ≤ B < 70%; C < 50%; NA means not tested.

[0762] Table 2

[0763] As can be seen from Table 2, the compounds of the present invention have excellent degradation performance for EGFR cells containing the L858R-T790M-C797S triple mutation and the 19del-T790M-C797S triple mutation.

[0764] Pharmacokinetic studies of compounds

[0765] Test Example 3 Pharmacokinetic Test in Male SD Rats

[0766] 3.1. Experimental animals

[0767] Three healthy adult male SD rats, 6-8 weeks old, weighing 200-300 g were used.

[0768] 3.2. Equipment and reagents

[0769] 3.2.1. Equipment

[0770] Analytical balance, animal weighing scale, magnetic stirrer, gavage needle, refrigerated centrifuge, single-channel manual pipette, liquid chromatography-mass spectrometry, etc.

[0771] Reagents

[0772] EDTA-Na2 anticoagulant: Weigh 11.2 g of EDTA-Na2 into a reagent bottle. Add 100 mL of normal saline and vortex to dissolve completely. Once prepared, aliquot into 1.5 mL centrifuge tubes, each containing approximately 20 μL, for whole blood sample collection.

[0773] 3.3. Experimental process

[0774] 3.3.1. Drug preparation

[0775] Accurately weigh approximately 10 mg of the sample to be tested and dissolve it in DMSO (10% of the total volume). Slowly add 0.5% MC solvent (90% of the total volume) while stirring. Ultrasonicate and vortex mix to obtain a visually uniform solution of the preparation at a concentration of 1 mg / mL. Prepare freshly before use.

[0776] A 0.2 mL sample was taken into a 1.5 mL centrifuge tube and stored at -80°C for concentration analysis of the dosing solution.

[0777] 3.3.2 Animal Preparation

[0778] Animals were housed in rat cages and fasted for at least 10 hours, but not water, starting the day before the experiment. On the day of the experiment, each animal was weighed and tail-marked. Blank blood was collected from each animal before dosing. Blood was collected from the tail vein.

[0779] 3.3.3. Drug administration

[0780] Route of administration: oral administration (po);

[0781] Dosing concentration: 1 mg / ml;

[0782] Dosage: 10 mg / kg;

[0783] Dosing volume: 10 mL / kg;

[0784] Operation procedure: Use your left hand wearing a bite-proof glove to catch the rat, make it stand upright, insert the gavage needle into the mouth and throat, and try to insert the needle when there is no obvious resistance, and then inject the drug into the stomach.

[0785] Sample collection

[0786] At 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, 0.1-0.2 ml of whole blood was collected from the animals in EDTA-Na2 anticoagulant tubes. The tubes were inverted 3-4 times to mix thoroughly. The supernatant plasma was separated by centrifugation at 2000 g for 5 minutes at 4°C and promptly transferred to -80°C for storage until testing. Blood was collected from the tail vein.

[0787] 3.5. Sample analysis and data processing

[0788] Sample analysis

[0789] Using Shimadzu liquid phase and Triple Quad TM 6500 + A quantitative assay for the test compound was established using AB mass spectrometry. The concentration of the unchanged drug in plasma was analyzed. The results were controlled for variation using quality control samples, which should have an accuracy between 80% and 120%.

[0790] Data processing

[0791] The main pharmacokinetic parameters were calculated using the non-compartmental model in Winnonlin Phoenix software, including the area under the concentration-time curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T 1 / 2 ), maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max )wait.

[0792] The results are shown in Table 3.

[0793] Table 3

[0794] It can be seen from Table 3 that the compounds of the present invention have good pharmacokinetic effects.

[0795] Test Example 4 Pharmacokinetic Test in CD-1 Mice

[0796] 4.1. Experimental Purpose

[0797] After a single oral administration of the test substance to CD-1 male mice, plasma was collected from the CD-1 mice. The plasma was sampled and analyzed to calculate the pharmacokinetic parameters.

[0798] 4.2. Test and Standard Product Information

[0799] The free base conversion factor calculation formula is: conversion factor CF = (MW / FW) * purity.

[0800] 4.3. Preparation

[0801] The vehicle is 5% DMSO + 10% Solutol HS-15 + 85% Saline.

[0802] Preparation process: Accurately weigh the compound powder, add appropriate volumes of DMSO, Solutol and saline in sequence, vortex and sonicate each step to finally form a uniform preparation solution.

[0803] Before administration, keep two samples of the preparation and the remaining preparation after administration, and store them at 2-8°C until mailing.

[0804] 4.4. Experimental Animals

[0805] Experimental animals were housed in an SPF-grade animal facility at Suzhou Xihua New Drug Development Co., Ltd. (Use Permit No. SYXK(Su)2021-0019). Animals were fed normally for at least 3 days before the experiment, and each mouse was labeled with a tail number. Animals in the oral administration group were fasted overnight before dosing and resumed feeding 4 hours after dosing, with free access to water. The sources and numbers of animals used in this experiment are shown in Table 4.

[0806] Table 4 Source and number of experimental animals

[0807] Experimental design

[0808] 1) The subjects were free to drink water before and after administration;

[0809] 2) All experiments were conducted according to the actual body weight of the animals;

[0810] 3) Administration: Oral administration (PO), fasting overnight before administration.

[0811] Before administration, check the state of the dosage formulation and ensure the uniformity of the formulation by vortexing, stirring or shaking. Calculate the theoretical dosage volume for each CD-1 mouse in each group according to the following formula.

[0812] 4.6. Sample collection and processing

[0813] The sample collection information is shown in Table 5.

[0814] Table 5 Sample collection information

[0815] Remark:

[0816] 1) The blood collection time window for blood collection within 1 hour (excluding the blood collection point before drug administration) is ±1 minute, and the blood collection time window for other time points is ±5%; 2) The sample is sent for testing.

[0817] At each time point listed in Table 5, 40 μL of whole blood was collected from the submandibular vein of the mouse and placed in a tube containing the anticoagulant EDTA-K2 (15% EDTA-K2 solution). The tube was stored on wet ice and centrifuged within 45 minutes (1,500 g, 2-8°C, 10 minutes) to collect plasma. The plasma was transferred to a pre-chilled centrifuge tube, snap-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or below until shipment.

[0818] 4.7. Experimental observation

[0819] During the experiment, any abnormal reactions of the animals were recorded in detail.

[0820] 4.8. Sample analysis and data processing

[0821] Sample analysis

[0822] A quantitative assay for the test compound was established using a Shimadzu liquid chromatography and Triple Quad™ 6500+AB mass spectrometer. The concentration of the unchanged drug in plasma was analyzed. The results were controlled for variation using quality control samples, with an accuracy of 80%-120%.

[0823] 4.8.2. Data processing

[0824] The main pharmacokinetic parameters were calculated using the non-compartmental model in Winnonlin Phoenix software, including the area under the concentration-time curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T1 / 2), maximum plasma concentration (Cmax), and time to maximum plasma concentration (Tmax).

[0825] The results are shown in Table 6.

[0826] Table 6

[0827] It can be seen from Table 6 that the compound of the present invention has excellent pharmacokinetic effects. Compared with Control Example 1-1, it has a higher exposure and better pharmacokinetic effects.

[0828] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, in, X3 is selected from none, NH, NR; X2 is selected from NR, O, S; Each R is independently selected from C 1-6 Alkyl, halogenated C 1-6 alkyl; X1 is selected from CH, N; X4 is selected from CH, N; Ring B is selected from the group consisting of a substituted or unsubstituted 6-7 membered heterocyclyl, a substituted or unsubstituted 7-9 membered heterospirocyclyl; wherein the substitution is that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl; Ring A is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 6-10 membered heteroaryl; the substitution means that 0-1 hydrogen atoms on the group are replaced by R6, and m hydrogen atoms are replaced by R7; m is 0, 1, or 2; in, R6 is selected from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, halogenated C 1-6 Alkyl, -P(O)RaRb, -C(O)R, -C(O)NHR, -C(O)NRaRb, -OC(O)-OR, -OC(O)NHR, -OC(O)NRaRb, -S(O)2R, -NR-S(O)2R, -NR-C(O)-OR, -NH-C(O)-OR, C 1-4 Alkyl-substituted or unsubstituted 4-7 membered heterocyclyl-O-; Ra and Rb are each independently C 1-6 Alkyl, C 3-6 Cycloalkyl, or Ra and Rb together with the heteroatom to which they are attached form a 5-7 membered heterocyclic ring; R7 is selected from the group consisting of H, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl; R1 is selected from halogen; R2 is selected from H, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted 2-6 membered heteroalkyl; wherein the heteroalkyl contains at least one heteroatom selected from the group consisting of O, N and S, wherein the substitution means that one or more hydrogen atoms on the group are replaced by a group selected from the group consisting of cyano, nitro, hydroxyl, amino and halogen; R3 is selected from halogen; Each R4 is independently H, halogen; Each R5 is independently H, halogen, C 1-6 Alkyl; or two R5 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; R8 is selected from: C 1-6 Alkyl, halogenated C 1-6 alkyl.

2. A compound, characterized in that The compound is a compound of formula II, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope compound or prodrug thereof, in, X3 is selected from the group consisting of none, NH, NR, O; X2 is selected from the group consisting of NR, O, S; Each R is independently selected from the following group: C 1-6 Alkyl, C 6-10 Aryl; X1 is selected from the group consisting of CH, N; X 11 Selected from the group consisting of: CH, N; X4 is selected from the following group: N, CR'; X5 is selected from the group consisting of CH, N, C; X 51 Selected from the group consisting of C-(OH), N, C; Ring B The present invention is selected from the following groups: substituted or unsubstituted 6-7 membered heteromonocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-9 membered heterobridged cycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-10 membered heterospirocycloalkylene containing 1-3 heteroatoms selected from N, O or S; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; Ring C The present invention is selected from the following groups: substituted or unsubstituted 6-7 membered heteromonocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 7-9 membered heterospirocycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 4-10 membered heterobridged cycloalkylene containing 1-3 heteroatoms selected from N, O or S, substituted or unsubstituted 5-7 membered heteroarylene containing 1-3 heteroatoms selected from N, O or S; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the following group: halogen, amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; Ring A is selected from the group consisting of: substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S; the substitution means that 1 hydrogen on the group is replaced by R6, and m hydrogens are replaced by R7; R6 is selected from the following group: C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, -P(O)RaRb, -C(O)Ra, -C(O)NRaRb, -OC(O)NRaRb, -S(O)2Ra, -NRa-S(O)2Rb, -NRa-C(O)-ORa, Ra and Rb are each independently selected from the group consisting of H, C 1-6 alkyl; R7 is selected from the group consisting of H, halogen, amino, nitro, hydroxy, cyano, C 1-6 Alkyl, halogenated C 1-6 alkyl, Hydroxyl substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl; R1 is halogen; R2 is selected from the group consisting of H, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 alkyl; R3 is halogen; R4 is selected from the group consisting of H, halogen; R5 is selected from the group consisting of H, halogen; R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 Alkyl; or R8 and R' and the atoms connected thereto together form a 5-6 membered heterocyclic group containing 1 O; L is selected from the following group: Each R' is independently selected from the group consisting of H, C 1-6 alkyl; m is selected from the following group: 0, 1, 2; n is selected from the following group: 0, 1, 2; n1 is selected from the following group: 0, 1, 2; m1 is selected from the following group: 0, 1, 2; m2 is selected from the following group: 0, 1, 2.

3. A compound of formula III, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, In the formula, X1 and X5 are each independently selected from CH, N, C; X2 is selected from NR, O and S; X3 is selected from the group consisting of no (bond), NH, NR and O; X4, X6 and X7 are each independently selected from the group consisting of CR or N; Each R is independently selected from the group consisting of H, halogen, hydroxy, amino, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 3-7 Cycloalkyl, C 3-7 Cycloalkyloxy, C 6-10 Aryl or C 6- 10 Aryloxy; L is m and n are each independently 0, 1, 2, 3 or 4; R7, R8 and the P to which they are connected together form Cy1, which is selected from the following group: a saturated or partially unsaturated 4-7 membered ring containing P=O, wherein the ring, in addition to P, also includes 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and the ring is optionally substituted with one or more substituents R a replace; or R7 and R8 are each independently selected from the following group: 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl; R a Selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl, 3 to 8 membered heterocyclic group, C 6-10 Aryl, 5-12 membered heteroaryl, -CN, -OR b 、-COR b 、-COOR b ,CONR b R c 、-NR b R c 、-NR b COR c or -NR b COOR c ,in, The alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl may be optionally replaced by R d replace; R b , R c and R d Each independently selected from the group consisting of hydrogen, hydroxyl, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl or C 3-8 Cycloalkyl; R1 is selected from halogen; R2 is selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, C 4-8 Heterocycloalkyl, -(C=O)-OC 1-6 Alkyl, -(C=O)-NH-C 1-6 Alkyl, halogen, -(CH2) p -C 1-4 Alkoxy, -(CH2) p -Halogenated C 1-4 Alkoxy, -(CH2) p -CN、C 1-6 Alkyl-substituted or unsubstituted 5-6-membered heteroaryl and 2-6-membered heteroalkyl containing 1-3 heteroatoms selected from N, O or S; wherein the heteroalkyl or heterocycloalkyl contains one or more heteroatoms independently selected from the following group: O, N and S; p is 0, 1, 2, or 3; R3 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 Hydroxyalkyl; R4 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 Hydroxyalkyl; R5 is selected from the group consisting of H, halogen, cyano, amino, nitro, hydroxyl, C 1-4 Alkyl, halogenated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or C 1-4 Hydroxyalkyl; Alternatively, R4 and R5 form a C3-6 carbocyclic ring or a 3-7 membered heterocyclic ring, wherein the heteroatom in the heterocyclic ring is selected from O, N or S; R6 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 Alkyl, or C 1-6 Hydroxyalkyl; or, X4 is CR, and R of X4 is connected to R6 to form a saturated or partially saturated 5-6-membered heterocyclic group containing 1 O; Ring B The substitution refers to the substitution of one or more hydrogen atoms on the group by a substituent selected from the group consisting of H, D, halogen, oxo (=O), amino, nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1- 6-Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5; Ring C The substituted or unsubstituted 6-7 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, or substituted or unsubstituted 7-12 membered heterospirocyclyl; the substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5; The heterocyclic group, heteroaryl group, heterospirocyclic group and heterobridged ring group each independently contain 1 to 3 heteroatoms selected from N, S and O.

4. The compound according to claim 3, characterized in that Ring B is selected from the group consisting of a substituted or unsubstituted 6-7 membered heterocyclylene group, or a substituted or unsubstituted 7-10 membered heterospirocyclylene group; preferably, ring B is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5.

5. The compound according to claim 3, characterized in that Ring C is a substituted or unsubstituted group selected from the group consisting of a 6-7 membered heterocyclylene group, a 5-6 membered heteroarylene group, or a 7-10 membered heterospirocyclylene group; preferably, ring C is a substituted or unsubstituted group selected from the following group: Wherein, the substitution is that one or more hydrogens on the group are replaced by a substituent selected from the group consisting of H, halogen, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or any two hydrogen atoms connected to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5; R a , R b and R as described in claim 3.

6. The compound according to claim 3, characterized in that The compound has a structure shown in Formula 2: In the formula, R', R" are each independently selected from the following group: D, halogen, oxo (=O), cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl; Or any two R' or two R" are connected to form a bond or -(CH2) q -, wherein q is 1, 2, 3, 4, or 5; or two R' or two R" attached to the same carbon atom may form a 3-6 membered saturated carbocyclic ring together with the attached carbon atom; m and n are each independently selected from the following group: 0, 1, 2, 3; X2, X3, X4, X5, X6, X7, L, Cy1, Ring C, R1, R2, R3, R4, R5, R6 are as defined in claim 3.

7. A compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, characterized in that: The compound is selected from the group consisting of:

8. A pharmaceutical composition, characterized in that The composition comprises (a) a therapeutically effective amount of the compound according to claim 1 or 2 or 3 or 7 as an active ingredient, and (b) a pharmaceutically acceptable carrier.

9. Use of a compound according to claim 1 or 2 or 3 or 7, characterized in that: For use selected from the group consisting of: 1) Preparation of drugs for regulating abnormal EGFR kinase activity; 2) preparing drugs for preventing and / or treating diseases associated with abnormal EGFR kinase activity or mutation (preferably, diseases associated with EGFR drug-resistant mutation); and / or 3) Prepare drugs for degrading EGFR protein.

10. The use according to claim 9, characterized in that The disease associated with abnormal EGFR kinase activity or mutation is selected from the group consisting of inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease, or a combination thereof.

Images