Compound for EGFR (epidermal growth factor receptor) protein degradation and application thereof

Abstract

The invention relates to a compound for EGFR (epidermal growth factor receptor) protein degradation and application thereof. Specifically, the compound disclosed by the invention has a structure as shown in a formula III, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses a preparation method of the compound and application of the compound in prevention and / or treatment of EGFR related diseases.

Description

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] HER family receptor tyrosine kinases are mediators of cell growth, differentiation and survival. The receptor family includes four different members, namely 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 EGFR activation regulation caused by overexpression or mutation is involved in various types of human cancers including colorectal cancer, pancreatic cancer, glioma, head and neck cancer and lung cancer, especially non-small cell lung cancer (NSCLC), and a variety of EGFR targeted agents have been developed over the years, and three generations of drugs have been used in clinical practice.

[0003] In actual clinical applications, patients will generally develop EGFR T790M resistance mutations within 8-12 months after using first- or second-generation EGFR inhibitors, causing the drug to lose its therapeutic effect. Although the third-generation EGFR inhibitors that were later launched, such as osimertinib and ametinib, can effectively overcome the resistance to EGFR T790M mutations, after a period of use, EGFR C797S and other resistance mutations will still appear, 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 urgently in the clinic. 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 resistance problem of C797S 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 EGFR protein-regulating drugs with greater clinical value 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]

[0010] in,

[0011] X3 is selected from none, NH, NR;

[0012] X2 is selected from NR, O, S;

[0013] Each R is independently selected from C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0014] X1 is selected from CH, N;

[0015] X4 is selected from CH, N;

[0016] 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;

[0017] 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;

[0018] in,

[0019] 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 1-4Alkyl-substituted or unsubstituted 4-7 membered heterocyclyl-O-;

[0020] 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;

[0021] 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;

[0022] R1 is selected from halogen;

[0023] 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;

[0024] R3 is selected from halogen;

[0025] Each R4 is independently H, halogen;

[0026] 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;

[0027] R8 is selected from: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0028] In another preferred embodiment, R6 is located at the adjacent position to the linking site.

[0029] In another preferred embodiment, ring A is selected from the following group:

[0030] Wherein, R6, R7, and m are as described in the first aspect of the present invention.

[0031] In another preferred embodiment, ring B is a substituted or unsubstituted group selected from the following group:

[0032] 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, C1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl.

[0033] 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.

[0034] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, C 1-6 Hydroxyalkyl, -P(O)R, -C(O)NHR, -C(O)NR, -OC(O)NHR, -OC(O)NR, -S(O)R, -NR-S(O)R, -NR-C(O)-OR, -NH-C(O)-OR;

[0035] 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.

[0036] In another preferred embodiment, the compound has a structure shown in Formula II-1:

[0037]

[0038] in,

[0039] X1 is selected from CH, N;

[0040] X2 is selected from NR;

[0041] R is selected from C 1-3 Alkyl, halogenated C 1-3 Alkyl (preferably CF3);

[0042] X3 is selected from none, NH;

[0043] R1 is selected from halogen;

[0044] 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;

[0045] R3 is selected from halogen;

[0046] Each R4 is independently H, halogen;

[0047] 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;

[0048] R6 is selected from the group consisting of:

[0049] R7 is selected from the following group: H, C 3-6 Cycloalkyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0050] R8 is selected from the following group: C 1-4 Alkyl, halogenated C 1-4 alkyl;

[0051] m is 0, 1, or 2.

[0052] In another preferred embodiment, R4 and R5 are not halogen at the same time.

[0053] In another preferred embodiment, R4 is F, and R5 is H.

[0054] In another preferred embodiment, R4 is H, and R5 is F.

[0055] In another preferred embodiment, R2 is ethyl.

[0056] In another preferred embodiment, R1 is Cl or Br.

[0057] In another preferred embodiment, R7 is H, Br, cyclopropyl, methoxy, ethyl, methyl, F, Cl, or isopropyl.

[0058] 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,

[0059]

[0060] in,

[0061] X3 is selected from the group consisting of none, NH, NR, O;

[0062] X2 is selected from the group consisting of NR, O, S;

[0063] Each R is independently selected from the following group: C 1-6 Alkyl, C 6-10 Aryl;

[0064] X1 is selected from the group consisting of CH, N;

[0065] X 11 Selected from the group consisting of: CH, N;

[0066] X4 is selected from the following group: N, CR';

[0067] X5 is selected from the group consisting of CH, N, C;

[0068] X 51 Selected from the group consisting of C-(OH), N, C;

[0069] 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;

[0070] 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;

[0071] 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;

[0072] R6 is selected from the following group: C 1-6 Alkyl, hydroxy substituted C1-6 Alkyl, -P(O)RaRb, -C(O)Ra, -C(O)NRaRb, -OC(O)NRaRb, -S(O)2Ra, -NRa-S(O)2Rb, -NRa-C(O)-ORa,

[0073]

[0074] Ra and Rb are each independently selected from the group consisting of H, C 1-6 alkyl;

[0075] 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;

[0076] R1 is halogen;

[0077] 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;

[0078] R3 is halogen;

[0079] R4 is selected from the group consisting of H, halogen;

[0080] R5 is selected from the group consisting of H, halogen;

[0081] 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;

[0082] L is selected from the following group:

[0083] Each R' is independently selected from the group consisting of H, C 1-6 alkyl;

[0084] m is selected from the following group: 0, 1, 2;

[0085] n is selected from the following group: 0, 1, 2;

[0086] n1 is selected from the following group: 0, 1, 2;

[0087] m1 is selected from the following group: 0, 1, 2;

[0088] m2 is selected from the following group: 0, 1, 2.

[0089] In another preferred embodiment, X3 is selected from the following group: none, NH, NR, O.

[0090] In another preferred embodiment, X3 is NH.

[0091] In another preferred embodiment, X2 is selected from the following group: NR, O, S.

[0092] In another preferred embodiment, X2 is -N(C 1-6 alkyl)-.

[0093] In another preferred embodiment, X1 is selected from the following group: CH, N.

[0094] In another preferred embodiment, X1 is N.

[0095] In another preferred embodiment, X 11 Selected from the group consisting of CH, N.

[0096] In another preferred embodiment, X 11 is N.

[0097] In another preferred embodiment, X4 is selected from the following group: N, CR'.

[0098] In another preferred embodiment, X4 is CH.

[0099] In another preferred embodiment, X5 is selected from the following group: CH, N, C.

[0100] In another preferred embodiment, X5 is selected from the following group: CH, C.

[0101] In another preferred embodiment, X 51 Selected from the group consisting of C-(OH), N, C.

[0102] In another preferred embodiment, X 51 is N.

[0103] In another preferred embodiment, ring A is

[0104] Wherein, R6, R7, and m are as described above.

[0105] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, hydroxy substituted C 1-6Alkyl, -P(O)RaRb, -C(O)NRaRb, -OC(O)NRaRb, -S(O)2Ra, -NRa-S(O)2Rb, -NRa-C(O)-ORa,

[0106]

[0107] In another preferred embodiment, R6 is selected from the following group: -P(O)RaRb, -C(O)NRaRb.

[0108] In another preferred embodiment, Ra and Rb are independently selected from the following groups: H, C 1-6 Alkyl, C 3-6 Cycloalkyl.

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

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

[0111] 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.

[0112] In another preferred embodiment, R2 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0113] In another preferred embodiment, R2 is C 1-6 alkyl.

[0114] 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 connected together form a 5-6 membered heterocyclic group containing 1 O.

[0115] In another preferred embodiment, R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0116] In another preferred embodiment, R8 is C 1-6 alkyl.

[0117] In another preferred embodiment, ring B is a substituted or unsubstituted group selected from the following group:

[0118] 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, C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0119] In another preferred embodiment, ring C Select from the following group:

[0120] In another preferred embodiment, L is selected from the following group:

[0121] 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':

[0122]

[0123]

[0124] in,

[0125] X1 is selected from the group consisting of CH, N;

[0126] X2 is NR;

[0127] R is C 1-3 alkyl;

[0128] X3 is selected from the group consisting of none, NH;

[0129] R1 is halogen;

[0130] 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;

[0131] R3 is halogen;

[0132] R 41 Selected from the group consisting of: H, halogen;

[0133] R 42Selected from the group consisting of: H, halogen;

[0134] R4 is selected from the group consisting of H, halogen;

[0135] R5 is selected from the group consisting of H, halogen;

[0136] R6 is selected from the group consisting of:

[0137] Ra and Rb are each independently selected from the group consisting of H, C 1-6 alkyl;

[0138] R7 is selected from the following group: H, C 3-6 Cycloalkyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy;

[0139] R8 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0140] m is selected from the following group: 0, 1, 2.

[0141] 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,

[0142]

[0143] In the formula,

[0144] X1 and X5 are each independently selected from CH, N, C;

[0145] X2 is selected from NR, O and S;

[0146] X3 is selected from the group consisting of no (bond), NH, NR and O;

[0147] X4, X6 and X7 are each independently selected from the group consisting of CR or N;

[0148] 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;

[0149] L is m and n are each independently 0, 1, 2, 3 or 4;

[0150] 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

[0151] R7 and R8 are each independently selected from the following group: 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Hydroxyalkyl;

[0152] 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;

[0153] 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;

[0154] R1 is selected from halogen;

[0155] 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 following group: O, N and S; p is 0, 1, 2, or 3;

[0156] 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;

[0157] 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;

[0158] 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;

[0159] 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;

[0160] 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;

[0161] 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, amino, oxo (=O), nitro, hydroxyl, cyano, C 1-6Alkyl, 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.);

[0162] 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;

[0163] The heterocyclic group, heteroaryl group, heterospirocyclic group and heterobridged ring group each independently contain 1 to 3 heteroatoms selected from N, S and O.

[0164] 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.

[0165] 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 heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -CN, -OR b 、-COR b 、-COOR b ,CONR b R c 、-NR b R c 、-NR b CORc or -NR b COOR c , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl are optionally replaced by R d replace;

[0166] R b , R c and R d Each independently selected from the group consisting of hydrogen, hydroxyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl or C 3-6 Cycloalkyl.

[0167] In another preferred embodiment, L is m and n are each independently 0, 1, or 2.

[0168] In another preferred embodiment, R6 is selected from the following group: C 1-6 Alkyl, halogenated C 1-6 alkyl.

[0169] In another preferred embodiment, R3 is selected from the following group: H or halogen.

[0170] In another preferred embodiment, R4 is selected from the following group: H or halogen.

[0171] In another preferred embodiment, R5 is selected from the following group: H or halogen.

[0172] 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.

[0173] 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 1-6 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.

[0174] In another preferred embodiment, the compound has a structure shown in Formula 2:

[0175]

[0176] In the formula,

[0177] X2, X3, X4, X5, X6, X7, L, Cy1, ring C, R1, R2, R3, R4, R5, R6 are as defined in the third aspect of the present invention.

[0178] In another preferred embodiment, the compound has a structure shown in Formula 2:

[0179]

[0180] In the formula,

[0181] 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;

[0182] 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;

[0183] 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;

[0184] m and n are each independently selected from the following group: 0, 1, 2, 3;

[0185] X2, X3, X4, X5, X6, X7, L, Cy1, ring C, R1, R2, R3, R4, R5, R6 are as defined in the third aspect of the present invention.

[0186] In another preferred embodiment, Select from the following group:

[0187] In another preferred embodiment, X1 is N.

[0188] In another preferred embodiment, X5 is CH.

[0189] In another preferred embodiment, the compound has a structure shown in Formula 3:

[0190]

[0191] In the formula,

[0192] 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.

[0193] In another preferred embodiment, the compound has a structure shown in Formula 4:

[0194]

[0195] In the formula,

[0196] X3, X5, L, Ring C, R1, R2, R3, R4, R5, R6 and R are as defined in the third aspect of the invention.

[0197] 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.

[0198] In another preferred embodiment, X2 is selected from NR, O and S; R is selected from the following group: CH3, phenyl, isopropyl, cyclopropyl.

[0199] In another preferred embodiment, R4 and R5 are each independently selected from the following group: H.

[0200] In another preferred embodiment, L is selected from the following group: ethylene,

[0201] In another preferred embodiment, X4 is selected from CH.

[0202] In another preferred embodiment, R2 is selected from ethyl.

[0203] In another preferred embodiment, R6 is selected from methyl.

[0204] In another preferred embodiment, R1 is selected from Cl and Br.

[0205] In another preferred embodiment, X3 is selected from NH.

[0206] In another preferred embodiment, X6 is selected from CR; R is selected from methoxy, cyclopropyl, and cyclopropyloxy.

[0207] In another preferred embodiment, X7 is selected from CH.

[0208] In another preferred embodiment, R3 is selected from H and F.

[0209] In a fourth aspect of the present invention, a compound is provided, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, wherein the compound is selected from the group consisting of:

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239] 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.

[0240] 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 %.

[0241] In another preferred embodiment, the dosage form of the pharmaceutical composition or preparation is an injection, tablet, capsule, pill, suspension or emulsion.

[0242] In another preferred embodiment, the dosage form of the pharmaceutical composition is injection, tablet, capsule, pill, suspension or emulsion; preferably injection.

[0243] In a sixth aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0244] (a1) first active ingredient: a therapeutically effective amount of the compound of the first / second / third / fourth aspect of the present invention;

[0245] (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, tanspiramycin, aspiramycin, IPI-504, NVP-AUY922; and

[0246] (b) a pharmaceutically acceptable carrier.

[0247] In the seventh aspect of the present invention, there is provided a use of the compound described in the first / second / third / fourth aspect of the present invention, for use selected from the following group:

[0248] 1) Preparation of drugs for regulating abnormal EGFR kinase activity;

[0249] 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

[0250] 3) Prepare drugs for degrading EGFR protein.

[0251] In another preferred embodiment, the abnormal EGFR kinase activity refers to EGFR kinase positive.

[0252] In another preferred embodiment, the abnormal EGFR kinase activity refers to overexpression of EGFR kinase.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] In another preferred embodiment, the EGFR-related disease is non-small cell lung cancer with an EGFR mutation selected from the following group: T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S.

[0257] In an eighth aspect of the present invention, a method for preventing and / or treating a disease associated with EGFR drug-resistant mutation is provided, comprising the steps of:

[0258] 1) determining the EGFR kinase activating mutation status of a subject in need thereof;

[0259] 2) When the subject's EGFR activating mutation status satisfies the treatment conditions, administering the compound of the first / second / third / fourth aspect of the present invention to the subject in need.

[0260] In another preferred embodiment, the "determining the patient's EGFR activating mutation status" is determined by cobas EGFR mutation assay v2.

[0261] In another preferred embodiment, the EGFR drug-resistant mutation-related disease is non-small cell lung cancer.

[0262] 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.

[0263] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0264] In another preferred embodiment, the method is in vitro.

[0265] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0266] After extensive and in-depth research, the inventor unexpectedly developed a compound with excellent EGFR degradation performance. The compound has a structure shown in Formula I, and has excellent inhibitory and / or therapeutic effects on EGFR-related diseases (especially EGFR resistance mutation-related diseases), and the compound has excellent pharmacokinetic properties. On this basis, the inventor completed the present invention.

[0267] the term

[0268] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0269] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0270] "Alkyl (alone or as part of another group)" refers to a monovalent straight or branched saturated hydrocarbon group containing 1 to 12 carbon atoms consisting only of carbon and hydrogen atoms. Alkyl is preferably 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, etc. In the present application, alkyl is also intended to include substituted alkyl, i.e., one or more positions in the alkyl are substituted, especially 1-4 substituents, which can 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 haloalkyl include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0271] "Alkylene" refers to a divalent radical of an alkyl group, for example, -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0272] "Alkoxy (alone or as part of another group)" refers to an alkyl group to which an oxy group is attached, which has an alkylO-structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1 to C6 alkoxy group. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like. "Haloalkoxy" refers to a group of the formula -OR, wherein 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.

[0273] "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 containing 2, 3, 4, 5 or 6 carbon atoms. Alkenyl includes, but is not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-butene-1-yl, etc. In the present invention, alkenyl includes substituted alkenyl.

[0274] "Alkenylene" refers to an alkenyl group having two points of attachment. For example, "vinylene" refers to the group -CH=CH-. Alkenylene can also be in unsubstituted form or in substituted form with one or more substituents.

[0275] "Alkynyl (alone or as part of another group)" refers to a straight or branched hydrocarbon chain containing more than 2 carbon atoms and characterized by having 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.

[0276] "Alkynylene" refers to an alkynyl group with two points of attachment. For example, "ethynylene" refers to the group: -C≡C-. Alkynylene can also be in unsubstituted form or in substituted form with one or more substituents.

[0277] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having 3-12, preferably 3-10, more preferably 3-8 ring atoms. The 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, etc.

[0278] "Cycloalkyloxy" refers to a radical of the formula -OR, where R is a cycloalkyl as defined herein. Exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. "Cycloalkylalkyl" refers to -(cycloalkyl)-alkyl, where the cycloalkyl and alkyl groups are as disclosed herein. "Cycloalkylalkyl" is bonded to the parent molecular structure through the cycloalkyl group.

[0279] "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 should be clear that the point of attachment of the heteroaryl group should be located 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, quinolyl, isoquinolyl, benzofuranyl, benzofuranyl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazine, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, aza Base, diazepine Heteroarylene refers to a heteroaryl group having two attachment sites.

[0280] "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.

[0281] "Heterocyclyl" refers to a monovalent group of a heterocyclic ring system, usually a stable monocyclic ring (such as 3-8 members, i.e. 3, 4, 5, 6, 7 or 8 members) or bicyclic ring (such as 5-12 members, i.e. 5, 6, 7, 8, 9, 10, 11 or 12 members) or polycyclic ring (such as 7-14 members, i.e. 7, 8, 9, 10, 11, 12, 13 or 14), including fused, spiro and / or bridged ring structures, which are saturated, partially unsaturated, and 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 heteroatoms, 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 (3) at least one ring is non-aromatic and contains heteroatoms and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl; and (4) 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. A heterocyclyl group refers to a heterocyclyl group having two attachment sites. In the present invention, preferably, the heterocyclyl group 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 heterocyclyl group is a 5-6-membered monocyclic heterocyclyl group or an 8-10-membered bicyclic heterocyclyl group.

[0282] "Heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl group, wherein the heterocyclyl group and the alkyl group are as defined above.

[0283] 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.

[0284] In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclic group and the like may be substituted or unsubstituted.

[0285] 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 should 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., monohalogen substituent or polyhalogen substituent, the latter such as trifluoromethyl or alkyl 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 may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic or aromatic rings, and R 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 It can independently represent hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, heterocycle or aromatic ring. The above typical substituents, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring can be optionally substituted. The 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 heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 urea group.

[0286] "Cyano" refers to a -CN group.

[0287] "Nitro" refers to -NO2.

[0288] "Hydroxyl" refers to -OH.

[0289] "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 It is an alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group.

[0290] "Halogen" refers to any halogen radical, for example, -F, -Cl, -Br or -I.

[0291] The term "deuterated compound" refers to a compound in which one or more hydrogen atoms (H) are replaced by deuterium atoms (D).

[0292] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0293] Compounds of formula I

[0294] 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.

[0295]

[0296] Wherein, each group is as defined in the third aspect of the present invention.

[0297] In one embodiment, any one of the groups in the compound is independently a corresponding group in the specific compound.

[0298] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is a salt formed by 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.

[0299] Another preferred salt is a salt of the compound of the present invention and 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.

[0300] The term "solvate" refers to a complex formed by the coordination of the compound of the present invention with solvent molecules in a specific ratio. "Hydrate" refers to a complex formed by the coordination of the compound of the present invention with water.

[0301] In addition, the compounds of the present invention also include prodrugs of the compounds shown in Formula I. The term "prodrug" includes a compound that can be biologically active or inactive, and when taken by an appropriate method, it undergoes metabolism or chemical reactions in the human body and is converted into a class of compounds of Formula I, or a salt or solution composed of a compound of Formula I. The prodrug includes (but is not limited to) carboxylate, carbonate, phosphate, nitrate, sulfate, sulfone, sulfoxide, amino compound, carbamate, azo compound, phosphoramide, glucoside, ether, acetal and the like forms of the compound.

[0302] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All these tautomers are part of the present invention.

[0303] All stereoisomers of the compounds (e.g., those due to asymmetric carbon atoms that may exist 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 simultaneously 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 two configurations, S or R, 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 diastereoisomers derived therefrom, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salt formation with an optically active acid.

[0304] The compounds of the present invention are prepared, separated and purified to obtain compounds with a weight content of equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compounds), which are listed in the text description. Such "very pure" compounds of the present invention are also considered part of the present invention.

[0305] All configurational isomers of the compounds of the present invention are within the scope of the invention, 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.

[0306] Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

[0307] Specific functional groups and chemical term definitions are detailed below. For 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 Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

[0308] 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. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

[0309] According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

[0310] 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 than the original atoms. 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, wherein the isotopes or other isotopic atoms of the above compounds are all within the scope of the present invention. Certain isotope-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 good metabolic stability in certain therapies has advantages, such as increasing half-life or reducing dosage in vivo, therefore, in some cases, can be preferred. Isotope-labeled compounds can be prepared by general methods, by replacing readily available isotope-labeled reagents with non-isotopic reagents, using the schemes disclosed in the examples.

[0311] If a synthesis of a specific enantiomer of the compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture can be separated, and the chiral auxiliary can be removed to obtain the pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a diastereomeric salt can be formed with a suitable optically active acid or base, and then separated by conventional means such as fractional crystallization or chromatography, and then the pure enantiomer can be obtained.

[0312] As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand their scope. Generally, the term "substituted" appears before or after the term "optional", and the general formula including substituents in the formulation of the present invention refers to replacing hydrogen free radicals with designated structural substituents. When multiple positions in a specific structure are substituted by multiple specific substituents, the substituents can be the same or different at each position. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have hydrogen substituents or any allowed organic compounds described above to supplement its valence. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way. The present invention believes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to compounds that are stable and that maintain the structural integrity of the compound over a period of time sufficient to be detected, and preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0313] 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.

[0314] 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 carried out by those skilled in the art to which the present invention belongs.

[0315] 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.

[0316] Usually, in the preparation process, each reaction is usually carried out under the protection of inert gas in a suitable solvent at 0 to 150° C., and the reaction time is usually 2 to 24 hours.

[0317] Pharmaceutical compositions and methods of administration

[0318] 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.

[0319] 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.

[0320] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0321] "Pharmaceutically acceptable carrier" refers 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, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0322] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0323] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0324] 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.

[0325] 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 starch 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.

[0326] Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0327] 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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0328] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0329] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0330] Compositions for parenteral injection may include 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.

[0331] Dosage forms for topical administration of the compounds of the 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.

[0332] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).

[0333] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0334] The compounds of formula I can be used in combination with other drugs known to treat or improve similar conditions. When administered in combination, the administration and dosage of the original drug can remain unchanged, and the compound of formula I can be taken simultaneously or subsequently. When the compound of formula I is taken simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I. Drug combination also includes taking the compound of formula I and one or more other known drugs in overlapping time periods. When the compound of formula I is used in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of them taken alone.

[0335] 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, tanspiramycin, aspiramycin, IPI-504, and NVP-AUY922.

[0336] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human or a mouse) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0337] Compared with the prior art, the main advantages of the present invention include:

[0338] (1) The compounds of the present invention have excellent EGFR degradation performance;

[0339] (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);

[0340] (3) The compounds of the present invention have excellent pharmacokinetic properties;

[0341] (4) The compounds of the present invention are suitable for preventing and / or treating diseases selected from the following group: EGFR-sensitive mutation cancers, diseases that have secondary drug resistance during current EGFR treatments;

[0342] (5) The compounds of the present invention have excellent safety;

[0343] (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.

[0344] 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 where specific conditions are not specified are 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 under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0345] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0346] Example 1-1: Synthesis of Compound TA-003

[0347] Synthesis of intermediate compound M1

[0348]

[0349] 1. Synthesis of Compound 2

[0350] In a 250 mL three-necked flask, 10 g SM1, 10.7 g boron trifluoride, 2.9 g pd(dppf)Cl2, and 8.2 g potassium carbonate were dissolved in 50 mL 1,4-dioxane and 10 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. TLC monitored the reaction until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 14.4 g of compound 2. LC-MS [M+1]: 198.

[0351] 2. Synthesis of Compound 3

[0352] 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, and the mixture was heated to 100°C under N2 protection and reacted overnight. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed, and 3.8 g of compound 3 was obtained by column chromatography. LC-MS [M+1]: 364.

[0353] 3. Synthesis of compound 4

[0354] In a 100 mL reactor, 3.8 g of compound 3 and 1.5 g of palladium carbon were dissolved in 35 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 2.9 g of compound 4. LC-MS [M+1]: 336.

[0355] 4. Synthesis of intermediate M1

[0356] 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, and the temperature was raised to 90°C under N2 protection, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until it was complete, and then quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 331 mg of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 496.

[0357] Synthesis of intermediate compound M2

[0358]

[0359] In a 250mL three-necked flask, 8.3g SM1 was dissolved in 100mL dichloromethane. Triethylamine was added under N2 protection, and the temperature was lowered to 0°C in an ice bath. TF2O was slowly added dropwise. The reaction was allowed to react 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 then dried. The sample was spin-dried and mixed, and 2g of intermediate M2 was obtained by column chromatography.

[0360] Synthesis of intermediate compound M3

[0361]

[0362] 1. Synthesis of Compound 2

[0363] In a 100 mL three-necked flask, 2 g SM1, 2.2 g pinacol borate, 2.4 g pd(dppf)Cl2, and 1.7 g potassium acetate were dissolved in 30 mL 1,4-dioxane, and the temperature was raised to 85°C under N2 protection. The reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete. The reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 2 g of compound 2. LC-MS [M+1]: 389.

[0364] 2. Synthesis of Compound 3

[0365] In a 250mL three-necked flask, 2g of compound 2, 2g of intermediate M2, 1.5g of sodium carbonate, and 376mg of pd(dppf)Cl2 were dissolved in 40mL of 1,4-dioxane and 10ml of H2O. The temperature was raised to 55°C under N2 protection and the reaction was continued for 2h. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with dichloromethane after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and mixed. 1.8g of compound 3 was obtained by column chromatography. LC-MS[M+1]: 480.

[0366] 3. Synthesis of compound 4

[0367] 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 reacted at room temperature overnight. TLC showed that the raw material disappeared, and the reaction solution was filtered to obtain 1 g of filter cake, which was compound 4. LC-MS [M+1]: 380.

[0368] 4. Synthesis of Compound 5

[0369] In a 100 mL three-necked flask, 1 g of compound 4 was dissolved in 10 mL of DMF. After N2 protection, 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. TLC monitored the reaction until it was complete. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 1.5 g of compound 5 was obtained by column chromatography. LC-MS [M+1]: 494.

[0370] 5. Synthesis of Compound 6

[0371] In a 100 mL reactor, 1.5 g of compound 5 and 228 mg of palladium carbon were dissolved in 30 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 200 mg of compound 6. LC-MS [M+1]: 496.

[0372] 6. Synthesis of intermediate M3

[0373] 200 g of compound 6 was added to a 100 mL reaction tube, dissolved in 1 mL of dichloromethane, 0.2 ml of trifluoroacetic acid was added, and the mixture was reacted at room temperature overnight. TLC showed that the starting material disappeared, and the reaction solution was concentrated to remove the solvent to obtain 283 mg of intermediate M3. LC-MS [M+1]: 440.

[0374] Synthesis of compound TA-003

[0375]

[0376] 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, and the mixture was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine and HATU were added with stirring, and the mixture was reacted in an ice-water bath for 1 hour under nitrogen protection. The mixture was naturally warmed to room temperature and reacted overnight. The reaction was complete when detected by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was dried. 80 mg of compound TA-003 was obtained by column chromatography. LC-MS [M+1]: 917.8.

[0377] 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).

[0378] Referring to the synthesis method of intermediate compound M1 and the synthesis method of compound TA-003, the following compounds were synthesized respectively:

[0379]

[0380] Example 1-2: Synthesis of Compound TA-005

[0381] Synthesis of intermediate compound M1

[0382]

[0383] In a 100mL single-necked flask, 500mg (2-aminophenyl) dimethylphosphine oxide was dissolved in 10mL isopropanol, 0.7ml 2,4,5-trichloropyrimidine and 2.9ml DIPEA were added in sequence, the temperature was raised to 100°C under N2 protection, the reaction was allowed to proceed overnight, and the reaction was monitored by TLC until it was complete. The reaction solution was directly dried and mixed, and 1g of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 317.

[0384] Synthesis of intermediate compound M2

[0385]

[0386] 1. Synthesis of Compound 2

[0387] In a 250 mL three-necked flask, 8.4 g SM1, 9 g boron trifluoride, 2.4 g pd(dppf)Cl2, and 6.9 g potassium carbonate were dissolved in 42 mL 1,4-dioxane and 8.4 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 5.3 g of compound 2. LC-MS [M+1]: 198.

[0388] 2. Synthesis of Compound 3

[0389] 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, and the mixture was heated to 100°C under N2 protection and reacted overnight. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed. 6.5 g of compound 3 was obtained by column chromatography. LC-MS [M+1]: 364.

[0390] 3. Synthesis of compound 4

[0391] In a 100 mL reactor, 6.5 g of compound 3 and 1.3 g of palladium carbon were dissolved in 70 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and 5.6 g of compound 4 was obtained by column chromatography. LC-MS [M+1]: 336.

[0392] 4. Synthesis of intermediate M2

[0393] 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, and the temperature was raised to 90°C under N2 protection. The reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete, and the reaction was quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 136 mg of intermediate M2 was obtained by column chromatography. LC-MS [M+1]: 515.

[0394] Synthesis of compound TA-005

[0395]

[0396] 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, and the mixture was cooled to 0°C in an ice-water bath. N,N-diisopropylethylamine and HATU were added with stirring, and the mixture was reacted in an ice-water bath for 1 hour under nitrogen protection. The mixture was naturally warmed to room temperature and reacted overnight. The reaction was complete when detected by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was dried. 18 mg of compound TA-005 was obtained by column chromatography, LC-MS [M+1]: 936.

[0397] 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).

[0398] Referring to the method of Example 1-2, the following compounds were synthesized:

[0399]

[0400]

[0401] The chiral compounds were separated by high pressure preparative chromatography as follows:

[0402]

[0403]

[0404] Example 1-3: Synthesis of Compound TC-159

[0405] Synthesis of intermediate compound M1

[0406]

[0407] 1. Synthesis of Compound 2

[0408] In a 50mL three-necked flask, 500mg of compound 1, 917mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787mg of sodium carbonate, and 181mg of pd(dppf)Cl2 were dissolved in 10mL of 1,4-dioxane and 1ml of H2O. The temperature was raised to 80°C under N2 protection and the reaction was allowed to proceed overnight. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with dichloromethane after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and mixed. 300mg of compound 2 was obtained by column chromatography. LC-MS[M+1]: 305

[0409] 2. Synthesis of Compound 3

[0410] In a 50 mg single-mouth bottle, add 300 mg of compound 2, 15 mg of palladium carbon catalyst, and 4 ml of methanol, mix well, and maintain the mixture after ventilation with a hydrogen balloon three times. After reacting at room temperature overnight, TLC detected that the reaction was complete, and the palladium carbon was removed by filtration through a diatomaceous earth pad. The mother liquor was dried by spin drying to obtain 100 mg of compound 3.

[0411] 3. Synthesis of intermediate M1

[0412] In a 100 ml reaction bottle, 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, and the temperature was raised to 90°C under N2 protection. The reaction was allowed to proceed overnight, and the reaction was monitored by TLC until it was complete. A small amount of saturated sodium bicarbonate aqueous solution was used for quenching, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin drying. 50 mg of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 486.

[0413] Synthesis of Compound TC-159

[0414]

[0415] 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

[0416] Synthesis of intermediate compound M1

[0417]

[0418] 1. Synthesis of Compound 2

[0419] 735 mg SM1, 317 mg dimethyl phosphine oxide, 12 ml DMF and 3 ml water were added to a 100 ml single-mouth bottle, mixed and replaced with nitrogen, and then 862 mg potassium phosphate, 60 mg palladium acetate and 151 mg Xantphos were added for nitrogen protection. The reaction was carried out at 120 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, purification was performed by column to obtain 283 mg of compound 2.

[0420] 2. Synthesis of intermediate compound M1

[0421] 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 in sequence, the temperature was raised to 100°C under N2 protection, the reaction was allowed to proceed overnight, and the reaction was monitored by TLC until it was complete. The reaction solution was directly dried and mixed, and 81 mg of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 368.

[0422]

[0423] Synthesis of intermediate compound M2

[0424] 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, and the temperature was raised to 90°C under N2 protection. The reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete, and a small amount of saturated sodium bicarbonate aqueous solution was used for quenching. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and dried by spin drying. 76 mg of intermediate M2 was obtained by column chromatography. LC-MS [M+1]: 567.

[0425] Synthesis of compound TA-007

[0426]

[0427] Referring to the synthesis method of TA-003 in Example 1-1, the intermediate M3 in Example 1-1 was used to synthesize compound TA-007. LC-MS [M+1]: 988.7.

[0428] Example 1-5: Synthesis of Compound TA-015

[0429] Synthesis of intermediate compound M1

[0430]

[0431] 1. Synthesis of Compound 2

[0432] In a 250 ml single-mouth bottle, add 3.8 g of compound 1, 5.2 ml of isopropyl pinacol ester, and 95 ml of tetrahydrofuran, stir and dissolve, cool to ice water bath for 10 minutes, slowly add 12 ml of isopropyl magnesium chloride, react at room temperature for 2 hours, add water to quench, extract with ethyl acetate, and purify by column to obtain 3.4 g of compound 2.

[0433] 2. Synthesis of intermediate M1

[0434] In 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, stirred evenly, 1g of tetrakistriphenylphosphine palladium was added under nitrogen protection, and the reaction was carried out at 80 degrees overnight. After column purification, 1.7g of intermediate M1 was obtained.

[0435] Synthesis of intermediate compound M2

[0436]

[0437] M2 was synthesized by referring to the synthesis method of intermediate M2 in Example 3. LC-MS [M+1]: 463.

[0438] Synthesis of compound TA-015

[0439]

[0440] Compound TA-015 was synthesized by referring to the synthesis method of TA-003 in Example 1-1. LC-MS [M+1]: 855.6.

[0441] Example 1-6: Synthesis of Compound TA-039

[0442] Synthesis of intermediate compound M1

[0443]

[0444] 1. Synthesis of Compound 2

[0445] In a 100 ml single-mouth bottle, 1 g of compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane were added, mixed and replaced with nitrogen, and then 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos were added for nitrogen protection. The reaction was carried out at 80 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, 705 mg of compound 2 was obtained by column purification.

[0446] 2. Synthesis of Compound 3

[0447] In a 100 ml single-mouth bottle, 500 mg of compound 2, 520 mg of cyclopropylboronic acid, and 5 ml of dioxane were added, and 1 ml of water was mixed and 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, 151 mg of compound 3 was obtained by column purification.

[0448] 3. Synthesis of intermediate M1

[0449] 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, stirred evenly, and nitrogen was protected, and the reaction was carried out at 100 degrees overnight. After column purification, 93 mg of intermediate M1 was obtained.

[0450] Synthesis of compound TA-039

[0451]

[0452] Referring to the synthesis method of TA-003 in Example 1-1, the intermediate M3 in Example 1-1 was used to synthesize compound TA-039. LC-MS [M+1]: 977.

[0453] Referring to the method of Examples 1-6, the following compounds were synthesized:

[0454]

[0455] Comparative Example 1-1: Synthesis of Comparative Example Compound C1

[0456] Synthesis of intermediate compound M1

[0457] The synthetic route is as follows:

[0458]

[0459] Intermediate M1 was synthesized by referring to the synthesis method of intermediate M1 in Example 1-1.

[0460] Synthesis of intermediate compound M2

[0461] The synthetic route is as follows:

[0462]

[0463] 1. Synthesis of Compound 2

[0464] In a 100 ml single-necked flask, compound 1 (1.0 g, 1.0 eq) and diboric acid pinacol ester (1.18 g, 1.2 eq), 1,4-dioxane 15 ml, potassium acetate (911 mg, 3.0 eq), PdCl2dppf (113 mg, 0.12 eq) were mixed evenly, replaced with nitrogen, heated to 85 ° C, and reacted overnight. TLC monitored the reaction until complete. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 1.2 g of compound 2. LC-MS [M+1]: 372.

[0465] 2. Synthesis of Compound 3

[0466] 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 evenly and protected with nitrogen. 80mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.12 equivalents) was added again, the temperature was raised to 55°C, and the reaction was carried out for 2 hours. TLC monitored the reaction until it was complete, filtered through a diatomaceous earth pad, and the mother liquor was collected. The mother liquor was evaporated to remove the solvent, and 30ml of water was added, and 15ml of ethyl acetate was extracted three times. The organic phases were combined and mixed, and passed through a column, and 500mg of compound 3 was obtained by column chromatography. LC-MS[M+1]: 462. .

[0467] 3. Synthesis of compound 4

[0468] 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 evenly. After replacing with a hydrogen balloon three times, the pressure was maintained at room temperature for 20 hours. TLC showed that the raw materials reacted completely. Filtered through a diatomaceous earth pad, the mother liquor was collected to obtain 400 mg of compound 4.

[0469] 4. Synthesis of Compound 5

[0470] 400 mg of compound 4 was added to a 100 ml single-necked flask, and 10 ml of tetrahydrofuran was added to dissolve it. A 4 M solution of dioxane hydrochloride was added dropwise in an ice-water bath, and the mixture was reacted at 40°C for 2 hours after the addition was complete. The solvent was removed by rotary evaporation to obtain 330 mg of compound 5. LC-MS [M+1]: 364.

[0471] 5. Synthesis of Compound 6

[0472] 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 to a 100 ml single-mouth bottle and stirred overnight at room temperature. TLC detected that the reaction was complete, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 370 mg of compound 6, LC-MS [M+1]: 479.

[0473] 6. Synthesis of intermediate M2

[0474] In a 100 ml single-necked bottle, 350 mg of compound 6 and 3 ml of dichloromethane were added dropwise, and 2 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature overnight. The reaction was completed by TLC detection. The solvent was removed by rotary evaporation to obtain 150 mg of M2. LC-MS [M-1]: 420.

[0475] Comparative Example 1-1 Synthesis of Compound C1

[0476] The synthetic route is as follows:

[0477]

[0478] Compounds M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml NN-dimethylformamide in a 50 ml round-bottom flask, and the mixture was cooled to 0°C in an ice-water bath. NN-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added with stirring, and the mixture was reacted in an ice-water bath for 1 hour under nitrogen protection. The mixture was naturally warmed to room temperature. The reaction was complete when detected 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.

[0479] 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).

[0480] Intermediate preparation example:

[0481] Synthesis of intermediate INT-1

[0482]

[0483] In a 100mL single-necked flask, 500mg (2-aminophenyl) dimethylphosphine oxide was dissolved in 10mL isopropanol, 0.7ml 2,4,5-trichloropyrimidine and 2.9ml DIPEA were added in sequence, the temperature was raised to 100°C under N2 protection, the reaction was allowed to proceed overnight, and the reaction was monitored by TLC until it was complete. The reaction solution was directly dried and mixed, and 1g of intermediate INT-1 was obtained by column chromatography. LC-MS [M+1]: 317.

[0484] Synthesis of intermediate compound INT-2

[0485]

[0486] 1. Synthesis of Compound 2

[0487] In a 250 mL three-necked flask, 8.4 g SM1, 9 g boron trifluoride, 2.4 g pd(dppf)Cl2, and 6.9 g potassium carbonate were dissolved in 42 mL 1,4-dioxane and 8.4 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 5.3 g of compound 2. LC-MS [M+1]: 198.

[0488] 2. Synthesis of Compound 3

[0489] 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, and the mixture was heated to 100°C under N2 protection and reacted overnight. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed. 6.5 g of compound 3 was obtained by column chromatography. LC-MS [M+1]: 364.

[0490] 3. Synthesis of intermediate INT-2

[0491] In a 100 mL reactor, 6.5 g of compound 3 and 1.3 g of palladium carbon were dissolved in 70 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and 5.6 g of intermediate INT-2 was obtained by column chromatography. LC-MS [M+1]: 336.

[0492] Synthesis of intermediate INT-3

[0493]

[0494] 1. Synthesis of Compound 2

[0495] In a 50mL three-necked flask, 500mg of compound 1, 917mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787mg of sodium carbonate, and 181mg of pd(dppf)Cl2 were dissolved in 10mL of 1,4-dioxane and 1ml of H2O. The temperature was raised to 80°C under N2 protection and the reaction was allowed to proceed overnight. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with dichloromethane after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and mixed. 300mg of compound 2 was obtained by column chromatography. LC-MS[M+1]: 305

[0496] 2. Synthesis of intermediate IN-3

[0497] In a 50 mg single-mouth bottle, add 300 mg of compound 2, 15 mg of palladium carbon catalyst, and 4 ml of methanol, mix well, and maintain the mixture after ventilation with a hydrogen balloon three times. After reacting at room temperature overnight, TLC detection shows that the reaction is complete. Filter the palladium carbon through a diatomaceous earth pad, and spin dry the mother liquor to obtain 100 mg of intermediate INT-3.

[0498] Synthesis of intermediate compound INT-4

[0499]

[0500] 1. Synthesis of Compound 2

[0501] 735 mg SM1, 317 mg dimethyl phosphine oxide, 12 ml DMF and 3 ml water were added to a 100 ml single-mouth bottle, mixed and replaced with nitrogen, and then 862 mg potassium phosphate, 60 mg palladium acetate and 151 mg Xantphos were added for nitrogen protection. The reaction was carried out at 120 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, purification was performed by column to obtain 283 mg of compound 2.

[0502] 2. Synthesis of intermediate compound INT-4

[0503] 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 in sequence, the temperature was raised to 100°C under N2 protection, the reaction was allowed to proceed overnight, and the reaction was monitored by TLC until it was complete. The reaction solution was directly dried and mixed, and 81 mg of intermediate INT-4 was obtained by column chromatography. LC-MS [M+1]: 368.

[0504] Synthesis of intermediate compound INT-5

[0505]

[0506] 1. Synthesis of Compound 2

[0507] In a 100 ml single-mouth bottle, 1 g of compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane were added, mixed and replaced with nitrogen, and then 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos were added for nitrogen protection. The reaction was carried out at 80 ° C overnight. TLC showed that the reaction was complete. After extraction with ethyl acetate, 705 mg of compound 2 was obtained by column purification.

[0508] 2. Synthesis of Compound 3

[0509] In a 100 ml single-mouth bottle, 500 mg of compound 2, 520 mg of cyclopropylboronic acid, and 5 ml of dioxane were added, and 1 ml of water was mixed and 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, 151 mg of compound 3 was obtained by column purification.

[0510] 3. Synthesis of intermediate INT-5

[0511] 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, stirred evenly, and nitrogen was protected, and the reaction was carried out at 100 degrees overnight. After column purification, 93 mg of intermediate INT-5 was obtained.

[0512] Synthesis of intermediate compound INT-6

[0513]

[0514] Dissolve 8.3 g SM1 in 100 mL dichloromethane in a 250 mL three-necked flask, add triethylamine under N2 protection, cool to 0°C in an ice bath, slowly add TF2O dropwise, react at room temperature overnight, monitor the reaction until completion by TLC, add water to the reaction solution, extract with EA, wash the organic phase with saturated NaCl and dry, spin dry and mix the sample, and obtain 2 g intermediate INT-6 by column chromatography.

[0515] Synthesis of intermediate compound INT-7

[0516]

[0517] Synthesis of compound 2

[0518] In a 250 ml single-mouth bottle, add 6.7 g SM1, 15.2 ml 1,2-dibromoethane, and 14.5 g potassium carbonate and dissolve in 67 ml ACN. Heat to 85 °C and react overnight. After TLC shows that the reaction is complete, the reaction solution is cooled to room temperature and then spin-dried and passed through a column to obtain 8.47 g of compound 2.

[0519] Synthesis of compound 3

[0520] Add 3g of compound 2 to a 250ml three-necked flask, dissolve it with 38ml of THF, and then protect it with nitrogen. Cool it down to -78℃ in a -80℃ environment, slowly drop 4ml of n-butyl lithium, and continue to react at -78℃ for 2h after the dropwise addition is complete, and stir at room temperature overnight. After TLC detection, quench with ammonium chloride in an ice bath, spin off the organic solvent, extract with ethyl acetate, dry the organic phase, spin dry, and pass through a column to obtain 1.2g of colorless oily compound 3.

[0521] Synthesis of compound 4

[0522] 1.2 g of compound 3 was added to a 100 ml single-mouth bottle, dissolved with 12 ml of ACN, stirred for 10 min under nitrogen protection in an ice bath, 1.7 g of NBS was added, and stirred at room temperature for 2 h. After the reaction was completed, 1.6 g of compound 4 was obtained by column chromatography purification.

[0523] Synthesis of compound 5

[0524] 1.6 g of compound 4 was dissolved in 13 ml of TFA in a 100 ml single-mouth bottle, and stirred for 10 min under nitrogen protection in an ice bath. Sodium nitrite was added and the temperature was naturally raised to room temperature for reaction overnight. After the reaction was complete by TLC, TFA was removed by concentration, and the remaining solution was quenched with saturated sodium bicarbonate, extracted with ethyl acetate, and the organic phase was dried and concentrated, and purified by column chromatography to obtain 874 mg of compound 5.

[0525] Synthesis of compound 6

[0526] 874 mg of compound 5, 212 mg of N-Boc piperazine, and 210 mg of potassium carbonate were added to a 10 ml reaction tube, dissolved in 4 ml of DMF, and heated at 65°C overnight under nitrogen protection. After the reaction was complete as detected by TLC, the reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to obtain 189 mg of compound 6.

[0527] Synthesis of compound 7

[0528] 189 mg of compound 6, 118 mg of C2H3BF3K, 91 mg of potassium carbonate, and 32 mg of Pd(dppf)Cl2 were added to a 10 ml reaction tube, dissolved with 2 ml of 1,4-dioxane, and then 0.4 ml of water was added. The mixture was protected by nitrogen and heated at 100°C for 4 h. After the reaction was complete by TLC, the reaction solution was cooled to room temperature and purified by column chromatography to obtain 135 mg of compound 7.

[0529] Synthesis of intermediate INT-7

[0530] 135 mg of compound 7 and 13 mg of palladium carbon were added to a 10 ml reaction tube, dissolved in 3 ml of methanol, protected by hydrogen, and reacted at room temperature overnight. After TLC detected that the reaction was complete, the palladium carbon was removed by suction filtration, and the filtrate was concentrated to obtain 137 mg of INT-7.

[0531] Synthesis of intermediate compound INT-8

[0532]

[0533] Synthesis of compound 2

[0534] 1 g SM1, 0.83 g tert-butyl bromoacetate, 2.2 g cesium carbonate, and 10 ml acetonitrile were added to a 100 ml single-mouth bottle. The temperature was raised to 55°C under nitrogen protection and the reaction was continued for 7 hours. After TLC showed that the reaction was complete, the solvent was removed by rotary evaporation, and the sample was mixed and passed through a column to obtain 1.4 g of a light yellow oily compound 2

[0535] Synthesis of compound 3

[0536] Add 200 mg SM2, 257 mg compound 2, 381 mg cesium carbonate, 64 mg Pd(dppf)Cl2, 10 ml 1,4-dioxane, and 1 ml water to a 100 ml single-mouth bottle. Heat to 90 °C under nitrogen protection and react overnight. After TLC shows that the reaction is complete, directly pass through the column to obtain 100 mg compound 3. LC-MS [M+1]: 471

[0537] Synthesis of compound INT-8

[0538] Dissolve 100 mg of compound 3 in 4 ml of dichloromethane in a 50 ml single-necked bottle, slowly drop 1 ml of trifluoroacetic acid, react at room temperature for 3 hours, and spin-dry the reaction solution as a crude product for the next step.

[0539] Synthesis of intermediate compound INT-9

[0540]

[0541] Synthesis of compound 2

[0542] In a 250ml single-mouth bottle, 5g of compound 1 and 5ml of ammonia water were heated in 10ml of n-butanol at 120°C for overnight reaction. After TLC showed that the reaction was complete, water and ethyl acetate were added to extract the reaction solution, and the organic phases were combined and dried by column. 3.8g of compound 2 was obtained.

[0543] Synthesis of compound 3

[0544] In a 100 ml single-mouth bottle, mix 1 g of compound 2 and 640 mg of phthalic anhydride, heat to 170 °C and stir for 6 hours in a molten state. Stop heating, cool to room temperature, add 20 ml of a 1:1 mixed solution of dichloromethane:methanol, and beat at room temperature for 30 minutes. Collect the filter cake by suction to obtain 1.3 g of white solid.

[0545] Synthesis of compound 4

[0546] Add 1g of compound 3, 510mg of phenylboronic acid, 750mg of copper acetate, 0.5ml of pyridine, and 50ml of dichloromethane to a 100ml single-mouth bottle. After mixing evenly, replace with an oxygen balloon three times. Keep the oxygen atmosphere to react overnight. After TLC shows that the reaction is complete, collect the mother liquor by suction filtration, spin dry, and purify by column to obtain 200mg of compound 4. LC-MS: 436

[0547] Synthesis of compound 5

[0548] Add 200 mg of compound 4, 10 ml of ammonia water and 10 ml of methanol to a 50 ml single-mouth bottle and stir overnight at room temperature. After TLC shows that the reaction is complete, remove the methanol by rotary evaporation, extract the reaction solution with ethyl acetate, combine the organic phases and purify by column to obtain 110 mg of white solid. LCMS: 306 / 308

[0549] Synthesis of compound 6

[0550] Mix 150 mg of compound 5 and 53 mg of acrylic acid in 5 ml of 2N hydrochloric acid, and add 16 mg of tetrabutylammonium bromide. Heat to 100°C under nitrogen protection and react overnight. After TLC shows that the reaction is complete, cool to room temperature and adjust the pH to 7-8 with a saturated sodium bicarbonate solution under an ice-water bath. Then adjust the pH to 5-6 with acetic acid. A large amount of solid precipitates and collects the filter cake 150 mg by suction filtration LCMS: 378

[0551] Synthesis of compound 7

[0552] Mix 150 mg of compound 6, 56 mg of sodium cyanate and 1.5 ml of acetic acid. Heat to 60°C and react overnight. Add 1.5 ml of 2N hydrochloric acid and keep for 3 hours. Turn off the heating and cool to room temperature to precipitate solids. Collect the filter cake by suction to obtain 80 mg of compound 7.

[0553] Synthesis of compound 8

[0554] 500 mg of compound 7, 632 mg of pinacol borate, 1.2 g of potassium acetate, and 45 mg of Pd(dppf)Cl2 were dispersed evenly in 1.4-dioxane. After nitrogen replacement three times, the temperature was raised to 80°C under nitrogen protection and reacted overnight. TLC showed that the raw materials reacted completely, and the sample was directly mixed and separated by column to obtain 560 mg of compound 8 LC-MS: 451.

[0555] Synthesis of compound 9

[0556] 560 mg of compound 8 and 538 mg of M3 of Example 2, 404 mg of sodium carbonate and 100 mg of Pd(dppf)Cl2 were dispersed uniformly in 6 ml of 1,4-dioxane and 0.6 ml of water. After nitrogen replacement, the mixture was heated to 55°C and reacted for 2 hours under nitrogen protection.

[0557] 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

[0558] Synthesis of compound 10

[0559] Disperse 340 mg of compound 9 in 6 ml of ethyl acetate, add 1.6 ml of hydrochloric acid / 1,4-dioxane, and react at room temperature for 4 hours. LC-MS shows that no starting material remains, and the reaction solution is spin-dried and used in the next step.

[0560] Synthesis of compound 11

[0561] 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

[0562] Synthesis of compound 12

[0563] 300 mg of compound 11 was added with 60 mg of palladium carbon catalyst, 3 ml of methanol and 3 ml of ethyl acetate, and then replaced with hydrogen three times. A hydrogen balloon was sealed and reacted at 35°C overnight. TLC showed that the reaction was complete. Filtered with celite pad, collected the mother liquor, and dried by column to obtain 170 mg of compound 12. LCMS: 558

[0564] Synthesis of compound INT-9

[0565] 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 by spin drying to obtain 150 mg of compound INT-9.

[0566] Synthesis of intermediate INT-10

[0567] The synthetic route is as follows:

[0568]

[0569] 1. Synthesis of Compound 2

[0570] In a 100 ml single-necked flask, compound 1 (1.0 g, 1.0 eq) and diboric acid pinacol ester (1.18 g, 1.2 eq), 1,4-dioxane 15 ml, potassium acetate (911 mg, 3.0 eq), PdCl2dppf (113 mg, 0.12 eq) were mixed evenly, replaced with nitrogen, heated to 85 ° C, and reacted overnight. TLC monitored the reaction until complete. Extracted with ethyl acetate, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain 1.2 g of compound 2. LC-MS [M+1]: 372.

[0571] 2. Synthesis of Compound 3

[0572] 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 evenly and protected with nitrogen. 80mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.12 equivalents) was added again, the temperature was raised to 55°C, and the reaction was carried out for 2 hours. TLC monitored the reaction until it was complete, filtered through a diatomaceous earth pad, and the mother liquor was collected. The mother liquor was evaporated to remove the solvent, and 30ml of water was added, and 15ml of ethyl acetate was extracted three times. The organic phases were combined and mixed, and passed through a column, and 500mg of compound 3 was obtained by column chromatography. LC-MS[M+1]: 462. .

[0573] 3. Synthesis of compound 4

[0574] 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 evenly. After replacing with a hydrogen balloon three times, the pressure was maintained at room temperature for 20 hours. TLC showed that the raw materials reacted completely. Filtered through a diatomaceous earth pad, the mother liquor was collected to obtain 400 mg of compound 4.

[0575] 4. Synthesis of Compound 5

[0576] 400 mg of compound 4 was added to a 100 ml single-necked flask, and 10 ml of tetrahydrofuran was added to dissolve it. A 4 M solution of dioxane hydrochloride was added dropwise in an ice-water bath, and the mixture was reacted at 40°C for 2 hours after the addition was complete. The solvent was removed by rotary evaporation to obtain 330 mg of compound 5. LC-MS [M+1]: 364.

[0577] 5. Synthesis of Compound 6

[0578] 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 to a 100 ml single-mouth bottle and stirred overnight at room temperature. TLC detected that the reaction was complete, and the mixture was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then subjected to column chromatography to obtain 370 mg of compound 6, LC-MS [M+1]: 479.

[0579] 6. Synthesis of intermediate INT-10

[0580] In a 100 ml single-necked bottle, 350 mg of compound 6 and 3 ml of dichloromethane were added dropwise, and 2 ml of trifluoroacetic acid was added. 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.

[0581] Synthesis of intermediate compound INT-11

[0582] The synthetic route is as follows:

[0583]

[0584] 1. Synthesis of Compound 2

[0585] In a 250 mL three-necked flask, 8.4 g SM1, 9 g boron trifluoride, 2.4 g pd(dppf)Cl2, and 6.9 g potassium carbonate were dissolved in 42 mL 1,4-dioxane and 8.4 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 5.3 g of compound 2. LC-MS [M+1]: 198.

[0586] 2. Synthesis of Compound 3

[0587] In a 50 ml single-mouth bottle, add 1 g of compound 2, 1.7 g of tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate, and 2.1 g of potassium carbonate, dissolve with 10 ml of dimethylacetamide, and then protect with nitrogen. Heat at 110°C for 5 h. After the reaction is complete as detected by TLC, the reaction solution is cooled to room temperature, water is added, and extracted with ethyl acetate. The organic phase is washed twice with saturated brine, dried, concentrated, and passed through a column to obtain 6 g of yellow solid compound 3. LC-MS[M+1]: 404.

[0588] 3. Synthesis of intermediate INT-11

[0589] Add 6g of compound 3 and 60mg of palladium carbon to a 100ml single-mouth bottle, dissolve in 60ml of anhydrous ethanol, protect with hydrogen, and react at room temperature. After the reaction is completed, remove the palladium carbon by suction filtration, and concentrate the filtrate to obtain 1.9g of intermediate INT-11. LC-MS [M+1]: 376.

[0590] Synthesis of intermediate compound INT-12

[0591]

[0592] Synthesis of compound 2

[0593] 1.15 g of tert-butyl acetate and 20 ml of dry tetrahydrofuran were mixed evenly, protected with nitrogen, cooled to -78°C, 11.8 ml of LDA was slowly added dropwise, and the reaction was kept warm for half an hour. 3 g of SM1 diluted in 20 ml of tetrahydrofuran was added dropwise again, and the low temperature was maintained for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phase was dried and filtered to obtain 4.38 g of compound 2.

[0594] Synthesis of compound 3

[0595] 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 with a diatomaceous earth pad and dried for later use.

[0596] Synthesis of compound 4

[0597] 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 to react overnight. After the reaction was completed under TLC monitoring, the sample was directly mixed and dried by spin column to obtain 50 mg of compound 4.

[0598] Synthesis of compound INT-12

[0599] 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 a crude compound INT-12.

[0600] Synthesis of intermediate compound INT-13

[0601]

[0602] Synthesis of compound 2

[0603] In a 100 ml single-mouth bottle, 500 mg SM1, 558 mg boc piperazine and 552 mg potassium carbonate were added and dissolved in 10 ml DMAC. The mixture was heated at 90°C and reacted overnight. After TLC showed that the reaction was completed, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate phase was dried, filtered and spin-dried through a column to obtain 760 mg of compound 2.

[0604] Synthesis of compound 3

[0605] In a 100 ml single-mouth 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, and the mixture was ventilated three times with a carbon monoxide balloon. After sealing with a balloon, the mixture was reacted at 85°C overnight. After TLC detection showed that the reaction was complete, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, and passed through a column to obtain 150 mg of a yellow oily compound 3. LC-MS [M+1]: 418

[0606] Synthesis of intermediate INT-13

[0607] In a 100 ml single-mouth bottle, add 150 mg of compound 3, 10 mg of palladium carbon, and 3 ml of methanol, mix, and react at 35 ° C overnight. After the reaction is completed, filter with diatomaceous earth pad, collect the mother liquor and spin dry to obtain crude compound INT-13.

[0608] Synthesis of intermediate compound INT-14

[0609] The synthetic route is as follows:

[0610]

[0611] 1. Synthesis of Compound 2

[0612] Add 10g magnesium chips and two iodine grains to a 500ml three-necked flask, and after N2 protection, add 150ml tetrahydrofuran to dissolve, add 0.1ml 1,4-dibromobutane to initiate, cool the reaction solution to 0℃, dissolve 12ml 1,4-dibromobutane in 40ml tetrahydrofuran, slowly drip, control the temperature to less than 30℃, after the dripping is complete, react at room temperature for 2-3 hours; cool the solution to 0℃, slowly drip 6.8ml diethyl phosphite, control the temperature to less than 20℃, after the dripping is complete, react at room temperature. After TLC shows that the reaction is over, cool the reaction solution to 0℃, slowly drip potassium carbonate solution (30g K2CO3 and 50g H2O) to quench, control the temperature to less than 10℃, a large amount of solid precipitates, filter, spin dry the filtrate through the column, and obtain 1.1g colorless transparent liquid compound 2. LC-MS[M+1]: 105.

[0613] 2. Synthesis of Compound 3

[0614] In a 100 ml single-mouth bottle, add 1.1 g of compound 2, 1.1 g of iodoaniline, 1.6 g of potassium phosphate, 152 mg of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene, and 59 mg of palladium acetate, dissolve with 24 ml of 1,4-dioxane, and then protect with nitrogen. Heat at 80°C to react overnight. After TLC detection of the reaction is complete, the reaction solution is cooled to room temperature, filtered, and the filtrate is dried by rotary evaporation. After column chromatography, 611 mg of brown oily compound 3 is obtained. LC-MS [M+1]: 196.

[0615] 3. Synthesis of intermediate INT-14

[0616] In a 100 ml single-mouth bottle, add 300 mg of compound 3, 649 mg of 2,4-dichloro-5-bromopyrimidine, and 1.5 ml of N,N-diisopropylethylamine, dissolve with 6 ml of isopropanol, and heat at 100°C under nitrogen protection. After the reaction is completed, 309 mg of intermediate INT-14 is obtained by column chromatography purification. LC-MS [M+1]: 388.

[0617] Synthesis of intermediate compound INT-15

[0618] The synthetic route is as follows:

[0619]

[0620] 1. Synthesis of Compound 2

[0621] In a 100 mL three-necked flask, 2 g SM1, 2.2 g pinacol borate, 2.4 g pd(dppf)Cl2, and 1.7 g potassium acetate were dissolved in 30 mL 1,4-dioxane, and the temperature was raised to 85°C under N2 protection. The reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete. The reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 2 g of compound 2. LC-MS [M+1]: 389.

[0622] 2. Synthesis of Compound 3

[0623] In a 250mL three-necked flask, 2g of compound 2, 2g of SM2, 1.5g of sodium carbonate, and 376mg of pd(dppf)Cl2 were dissolved in 40mL of 1,4-dioxane and 10ml of H2O. The temperature was raised to 55°C under N2 protection and the reaction was continued for 2h. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with dichloromethane after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was spin-dried and mixed. 1.8g of compound 3 was obtained by column chromatography. LC-MS[M+1]: 480.

[0624] 3. Synthesis of Compound 4

[0625] 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 reacted at room temperature overnight. TLC showed that the raw material disappeared, and the reaction solution was filtered to obtain 1 g of filter cake, which was compound 4. LC-MS [M+1]: 380.

[0626] 4. Synthesis of Compound 5

[0627] In a 100 mL three-necked flask, 1 g of compound 4 was dissolved in 10 mL of DMF. After N2 protection, 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. TLC monitored the reaction until it was complete. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 1.5 g of compound 5 was obtained by column chromatography. LC-MS [M+1]: 494.

[0628] 5. Synthesis of Compound 6

[0629] In a 100 mL reactor, 1.5 g of compound 5 and 228 mg of palladium carbon were dissolved in 30 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 200 mg of compound 6. LC-MS [M+1]: 496.

[0630] 6. Synthesis of intermediate INT-15

[0631] 200 g of compound 6 was added to a 100 mL reaction tube, dissolved in 1 mL of dichloromethane, 0.2 ml of trifluoroacetic acid was added, and the mixture was reacted at room temperature overnight. TLC showed that the starting material disappeared, and the reaction solution was concentrated to remove the solvent to obtain 283 mg of intermediate INT-15. LC-MS [M+1]: 440.

[0632] Synthesis of intermediate compound INT-16

[0633] The synthetic route is as follows:

[0634]

[0635] 1. Synthesis of Compound 2

[0636] In a 100mL three-necked flask, 1g of SM1 was dissolved in 20ml of DMF, and then 260mg of sodium hydride and 810mg of 2-iodopropane were added under nitrogen protection under ice bath, and the mixture was reacted at room temperature for 1h. TLC monitored the reaction until it was complete, and the reaction solution was quenched with saturated ammonium chloride, and water was added and extracted with EA. The organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed, and 776mg of compound 2 was obtained by column chromatography. LC-MS[M+1]: 274.

[0637] 2. Synthesis of Compound 3

[0638] In a 250mL three-necked flask, 776mg of compound 2, 0.3ml of acrylic acid, and 92mg of tetrabutylammonium bromide were dissolved in 8mL of 2M hydrochloric acid solution, and the temperature was raised to 100°C under N2 protection, and the reaction was allowed to proceed overnight. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, quenched with saturated sodium carbonate in an ice bath, and the pH was 9. The pH was then adjusted to 3-4 with acetic acid, and a large amount of white solid precipitated. After sufficient stirring, the mixture was filtered, and the filter cake was dried to obtain 1.2g of compound 3. LC-MS[M+1]: 346.

[0639] 3. Synthesis of Compound 4

[0640] In a 100mL single-necked flask, 1.2g of compound 3 was dissolved in 12mL of acetic acid, 453mg of sodium cyanate was added, and the mixture was heated at 60℃ for 14h. 12ml of 2M hydrochloric acid solution was added, and the mixture was reacted at 60℃ for 3h. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, quenched with saturated sodium carbonate solution, and water was added to extract with ethyl acetate. The organic phase was dried and concentrated, and 330mg of compound 4 was obtained by column chromatography. LC-MS[M+1]: 369.1.

[0641] 4. Synthesis of Compound 5

[0642] In a 100 mL three-necked flask, 330 mg of compound 4, 340 mg of diboronic acid pinacol ester, 65 mg of pd(dppf)Cl2, and 262 mg of potassium acetate were dissolved in 7 mL of 1,4-dioxane, and the temperature was raised to 85°C under N2 protection. The reaction was allowed to proceed overnight. TLC was used to monitor the reaction until it was complete. The reaction solution was cooled to room temperature, and the insoluble impurities were removed by suction. The filtrate was dried by rotary evaporation and mixed with a sample, and 434 mg of compound 5 was obtained by column chromatography. LC-MS [M+1]: 417.

[0643] 5. Synthesis of Compound 6

[0644] In a 50 ml single-mouth 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. The temperature was raised to 55°C under N2 protection and the reaction was continued for 2 h. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was dried, and the sample was mixed by spin drying. 265 mg of compound 6 was obtained by column chromatography. LC-MS [M+1]: 508.

[0645] 6. Synthesis of Compound 7

[0646] In a 50 mL single-necked flask, 265 mg of compound 6 was dissolved in 3 mL of ethyl acetate, and 2 mL of 1,4-dioxane hydrochloride was added. The mixture was reacted at room temperature overnight. TLC showed that the raw material disappeared. The reaction solution was filtered to obtain 142 mg of filter cake, which was compound 7. LC-MS [M+1]: 408.

[0647] 7. Synthesis of Compound 8

[0648] In a 50 mL single-necked flask, 142 mg of compound 7 was dissolved in 3 mL of DMF. After N2 protection, 0.28 ml of N,N-diisopropylethylamine was added. After stirring for 10 min in an ice bath, 0.06 ml of tert-butyl bromoacetate was added. The reaction was allowed to react overnight at room temperature. TLC monitored the reaction until it was complete. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 174 mg of compound 8 was obtained by column chromatography. LC-MS [M+1]: 522.4.

[0649] 8. Synthesis of Compound 9

[0650] In a 50 mL single-mouth bottle, 174 mg of compound 8 and 17 mg of palladium carbon were dissolved in 4 mL of methanol and 4 mL of ethyl acetate, and the mixture was reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 142 mg of compound 9. LC-MS [M+1]: 524.

[0651] 9. Synthesis of intermediate INT-16

[0652] 142 mg of compound 9 was added to a 10 mL reaction tube, dissolved in 2 mL of dichloromethane, and 2 ml of trifluoroacetic acid was added to react at room temperature overnight. TLC showed that the starting material disappeared, and the reaction solution was concentrated to remove the solvent to obtain 265 mg of intermediate INT-16. LC-MS [M+1]: 468.2.

[0653] Synthesis of intermediate INT-17

[0654] The synthetic route is as follows:

[0655]

[0656] 1. Synthesis of Compound 2

[0657] 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 evenly and protected with nitrogen. 63mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 equivalent) was added again, nitrogen was replaced three times and the temperature was raised to 100°C, and the reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete, filtered through a diatomaceous earth pad, the mother liquor was collected, the mother liquor was evaporated to remove the solvent, 30ml of water was added, and 15ml of ethyl acetate was extracted three times. The organic phases were combined and mixed, and passed through a column, and 345mg of compound 2 was obtained by column chromatography.

[0658] 2. Synthesis of Compound 3

[0659] In a 50 ml single-mouth bottle, 345 mg of compound 2 and 34.5 mg of Pd / C were added to 3.4 ml of MeOH, hydrogen was replaced three times, and the mixture was reacted at room temperature for 6 h under the protection of a hydrogen balloon. After the reaction was completed, the reaction solution was filtered to remove palladium carbon. The filtrate was evaporated to remove the solvent to obtain 345 mg of compound 3. LC-MS [M+1]: 446.

[0660] 3. Synthesis of compound 4

[0661] In a 50 ml single-mouth bottle, 345 mg of compound 3 and 2 ml of hydrochloric acid-tetradioxane solution were added to 3 ml of THF and reacted at room temperature for 6 h. After the reaction was complete, it was directly evaporated to dryness for subsequent reactions. LC-MS [M+1]: 346.

[0662] 4. Synthesis of Compound 5

[0663] In a 100 mL three-necked flask, 690 mg of compound 4 was dissolved in 7 mL of DMF. After N2 protection, 3.5 mL of N,N-diisopropylethylamine was added. After stirring for 10 min in an ice bath, 470 mg of tert-butyl bromoacetate was added. The reaction was allowed to react overnight at room temperature. TLC monitored the reaction until it was complete. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 690 mg of compound 5 was obtained by column chromatography. LC-MS [M+1]: 460.

[0664] 5. Synthesis of intermediate INT-17

[0665] 363 mg of compound 6 was added to a 100 mL reaction tube, dissolved in 1 mL of dichloromethane, and 0.2 ml of trifluoroacetic acid was added to react at room temperature overnight. TLC showed that the starting material disappeared, and the reaction solution was concentrated to remove the solvent to obtain 318 mg of intermediate INT-17. LC-MS [M+1]: 404.

[0666] Synthesis of intermediate INT-18

[0667]

[0668] Synthesis of compound 2

[0669] In a 250 mL three-necked flask, 2.0 g SM1 and 1.06 g dimethylphosphine were dissolved in 20 mL NN-dimethylformamide. Under N2 protection, 2.9 g potassium phosphate, 204 mg palladium acetate and 525 mg Xnatphos were added. After nitrogen replacement three times, the mixture was reacted at 115 °C overnight. 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 then dried. The sample was spin-dried and mixed, and 350 mg of compound 2 was obtained by column chromatography.

[0670] Synthesis of intermediate INT-18

[0671] In a 100 ml single-mouth bottle, add 300 mg of compound 2, 649 mg of trichloropyrimidine, and 1.5 ml of N,N-diisopropylethylamine, dissolve with 6 ml of isopropanol, and heat to 100°C for reaction under nitrogen protection. After the reaction, 309 mg of intermediate INT-18 was obtained by column chromatography purification. LC-MS [M+1]: 318.

[0672] Synthesis of intermediate compound INT-19

[0673] The synthetic route is as follows:

[0674]

[0675] 1. Synthesis of Compound 2

[0676] In a 500mL three-necked flask, 29g of SM1 was dissolved in 290ml of anhydrous ethanol, and then 35ml of methylhydrazine was added under nitrogen protection, and the mixture was heated at 80°C for reaction. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature and stirred thoroughly in an ice bath. A large amount of white solid precipitated, and a filter cake was obtained by suction filtration. After drying the filter cake, 15.7g of the product was obtained; 9g of the product was obtained by column chromatography of the filtrate; a total of 24.7g of light yellow solid compound 2 was obtained. LC-MS[M+1]: 246.1.

[0677] 2. Synthesis of Compound 3

[0678] In a 500mL three-necked flask, 24.7g of compound 2, 10.4ml of acrylic acid, and 3.2g of tetrabutylammonium bromide were dissolved in 250mL of 2M hydrochloric acid solution, and the temperature was raised to 100°C for overnight reaction. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, quenched with saturated sodium carbonate in an ice bath, and the pH was 9, and then adjusted to 3-4 with acetic acid, and a large amount of white solid precipitated. After sufficient stirring, it was filtered, and the filter cake was dried to obtain 26g of yellow solid compound 3. LC-MS [M+1]: 316.1.

[0679] 3. Synthesis of intermediate INT-19

[0680] 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 solution was added, and the mixture was reacted at 60°C for 3h. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature and stirred thoroughly in an ice bath. A large amount of white solid precipitated, which was filtered and the filter cake was dried to obtain 10.7g of yellow solid INT-19. LC-MS[M+1]: 342.

[0681] Example 2-1: Synthesis of Compound TB-006

[0682]

[0683] The synthetic route is as follows:

[0684]

[0685] 1. Synthesis of Compound 2

[0686] In a 10 ml reaction tube, 100 mg of intermediate INT-14, 97 mg of intermediate INT-11, and 46 mg of zinc chloride were added in sequence, dissolved with 2 ml of isopropanol, protected by nitrogen, and heated at 105°C for overnight reaction. After TLC detection of the reaction was complete, the reaction solution was cooled to room temperature, quenched with saturated sodium bicarbonate, extracted with ethyl acetate, the organic phase was dried and concentrated, and purified by column chromatography to obtain 73 mg of compound 2. LC-MS [M+1]: 726.

[0687] 2. Synthesis of Compound 3

[0688] 73 mg of compound 2 and 1 ml of trifluoroacetic acid were added to a 10 ml reaction tube, dissolved in 2 ml of dichloromethane, and reacted at room temperature for 0.5 h. After TLC detection of the reaction was complete, the reaction solution was concentrated to remove the solvent to obtain 58 mg of compound 3. LC-MS [M+1]: 627.

[0689] 3. Synthesis of Compound TB-006

[0690] Add 116 mg of intermediate INT-15 to a 10 ml reaction tube, dissolve it with 2 ml of DMF, add 0.15 ml of DIPEA, protect with nitrogen, stir for 10 min in an ice bath, add 58 mg of compound 3 and 45 mg of HATU, and react at room temperature overnight. After TLC detection, add water to the reaction solution and extract with ethyl acetate, wash the organic phase twice with saturated brine, dry and concentrate, and purify by column chromatography to obtain 17 mg of compound TB-006. LC-MS [M+1]: 1047 HPLC: 96%

[0691] 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).

[0692] 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:

[0693]

[0694] The chiral compounds were separated by high pressure preparative chromatography as follows:

[0695]

[0696]

[0697] Example 2-2: Synthesis of Compound TB-008

[0698]

[0699] The synthetic route is as follows:

[0700]

[0701] In a 50mL round-bottom flask, 50mg of compound 3 and 75mg of INT-17 were dissolved in 3mL of DMF, and then 0.14ml of DIPEA and 40mg of HATU were added. After N2 ventilation for three times, the reaction was allowed to react at room temperature for 3h. TLC detected that the reaction was complete. The reaction solution was extracted with ethyl acetate and water, and then dried under reduced pressure and mixed. 19mg of compound TB-008 was obtained by column chromatography. LC-MS [M+1]: 1012.5. 1H 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).

[0702] Referring to the synthesis method of compound TB-008, the following compounds were synthesized:

[0703]

[0704] Example 2-3: Synthesis of Compound TB-018

[0705]

[0706] The synthetic route is as follows:

[0707]

[0708] Synthesis of compound TB-018

[0709] 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. The mixture was stirred for 10 min under nitrogen protection in an ice bath, and 50 mg of compound 3 and 39 mg of HATU were added. The mixture was reacted overnight at room temperature. After TLC detection showed that the reaction was complete, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried, concentrated, and purified by column chromatography to obtain 22 mg of compound TB-018. LC-MS [M+1]: 1077 HPLC: 99.14%

[0710] 1 H 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).

[0711] Referring to the synthesis method of compound TB-018, the following compounds were synthesized:

[0712]

[0713] Embodiment 2-4:

[0714]

[0715] Synthesis of intermediate compound M2

[0716]

[0717] 1. Synthesis of Compound 2

[0718] In a 250 mL three-necked flask, 8.4 g SM1, 9 g potassium vinyl trifluoroborate, 2.4 g pd(dppf)Cl2, and 6.9 g potassium carbonate were dissolved in 42 mL 1,4-dioxane and 8.4 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. The reaction was monitored by TLC until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 5.3 g of compound 2. LC-MS [M+1]: 198.

[0719] 2. Synthesis of Compound 3

[0720] In a 250 mL three-necked flask, 0.3 g of compound 2, 609 mg of 4-tert-butyloxycarbonylaminopiperidine and 631 mg of potassium carbonate were dissolved in 10 mL of DMAC, and the mixture was heated to 100° C. under N2 protection and reacted overnight. TLC showed that the raw material disappeared. The reaction solution was cooled to room temperature, filtered to remove insoluble impurities, the filtrate was extracted with EA after adding water, the organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed, and 400 mg of compound 3 was obtained by column chromatography. LC-MS [M+1]: 378.

[0721] 3. Synthesis of compound 4

[0722] In a 100 mL single-mouth bottle, 400 mg of compound 3 and 20 mg of palladium carbon were dissolved in 10 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 340 mg of compound 4. LC-MS [M+1]: 350.

[0723] 4. Synthesis of intermediate M2

[0724] 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, and the temperature was raised to 90°C under N2 protection. The reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete, and the reaction was quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 70 mg of intermediate M2 was obtained by column chromatography. LC-MS [M+1]: 529.

[0725] Synthesis of compound TC-085

[0726]

[0727] 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, and 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 for 1 hour under nitrogen protection. The mixture was naturally warmed to room temperature and reacted overnight. The reaction was complete when detected by TLC. The mixture was extracted with dichloromethane and water, and the organic phase was dried. 18 mg of TC-085 was obtained by column chromatography. LC-MS [M+1]: 950.7.

[0728] 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).

[0729] Referring to the synthesis method of intermediate compound M2 and the synthesis method of compound TC-085, the following compounds were synthesized respectively:

[0730]

[0731]

[0732]

[0733]

[0734]

[0735] The chiral compounds were separated by high pressure preparative chromatography as follows:

[0736] Example 2-5: Synthesis of Compound TC-113

[0737]

[0738] Synthesis of Compound TC-113

[0739]

[0740] 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).

[0741] Example 2-6: Synthesis of Compound TC-117

[0742]

[0743] Synthesis of Compound TC-117

[0744]

[0745] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-117 was synthesized

[0746] LC-MS[M+1]: 916.5 1H NMR (400MHz, 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=6.7Hz,2H),3.71(s,3H) ,3.60–3.48(m,1H),3.19(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),2.6 0(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).

[0747] Referring to the synthesis method of compound TB-006 in Example 2-1, the following compounds were synthesized respectively:

[0748]

[0749] Example 2-7: Synthesis of Compound TC-123

[0750]

[0751] Synthesis of intermediate compound M1

[0752]

[0753] Synthesis of compound 2

[0754] In a 100 ml single-mouth bottle, 500 mg SM1, 558 mg boc piperazine and 552 mg potassium carbonate were added and dissolved in 10 ml DMAC. The mixture was heated at 90°C and reacted overnight. After TLC showed that the reaction was completed, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate phase was dried, filtered and spin-dried through a column to obtain 760 mg of compound 2.

[0755] Synthesis of compound 3

[0756] In a 100 ml single-mouth 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, and the mixture was ventilated three times with a carbon monoxide balloon. After sealing with a balloon, the mixture was reacted at 85°C overnight. After TLC detection showed that the reaction was complete, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, and passed through a column to obtain 150 mg of a yellow oily compound 3. LC-MS [M+1]: 418

[0757] Synthesis of compound 4

[0758] In a 100 ml single-mouth bottle, add 150 mg of compound 3, 10 mg of palladium carbon, and 3 ml of methanol, mix, and react at 35 °C overnight. After the reaction is completed, filter with diatomaceous earth pad, collect the mother liquor and spin dry to obtain crude compound 4.

[0759] Synthesis of intermediate M1

[0760] In a 100 ml single-mouth bottle, 112 mg of intermediate pyrimidine, 130 mg of compound 4, 87 mg of p-toluenesulfonic acid monohydrate, and 4 ml of isopropanol were heated to 90°C for overnight reaction. After the reaction was completed, 60 mg of intermediate M1 was obtained by column chromatography purification.

[0761] Synthesis of Compound TC-123

[0762]

[0763] Compound TC-123 was synthesized by referring to the synthesis method of compound TB-006 in Example 2-1.

[0764] 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)

[0765] Referring to the synthesis method of intermediate compound M1 and the synthesis method of compound TC-123, the following compounds were synthesized respectively:

[0766]

[0767] Example 2-8: Synthesis of Compound TC-135

[0768] TC-135

[0769]

[0770] Synthesis of Compound TC-135

[0771]

[0772] Add 278 mg of intermediate INTC-15 to a 10 ml reaction tube, dissolve it with 2 ml of DMF, add 0.4 ml of DIPEA, protect with nitrogen, stir for 10 min in an ice bath, add 115 mg of intermediate M1 and 107 mg of HATU, and react at room temperature overnight. After TLC detection, add water to the reaction solution and extract with ethyl acetate, wash the organic phase twice with saturated brine, dry and concentrate, and purify by column chromatography to obtain 10 mg of compound TC-135. LC-MS [M+1]: 949.8 HPLC: 95.49%

[0773] 1H 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).

[0774] Example 2-9: Synthesis of Compound TC-144

[0775]

[0776] Synthesis of Compound TC-144

[0777]

[0778] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-144 was synthesized.

[0779] 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).

[0780] Referring to the synthesis method of compound TC-144 in Example 2-9, the following compounds were synthesized respectively:

[0781]

[0782] Example 2-10: Synthesis of Compound TC-150

[0783]

[0784] Synthesis of Compound TC-150

[0785]

[0786] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-150 was synthesized.

[0787] 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).

[0788] Example 2-11: Synthesis of Compound TC-215

[0789]

[0790]

[0791] Referring to the synthesis method of compound TB-006 in Example 2-1, compound TC-150 was synthesized.

[0792] 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).

[0793] Example 2-12: Synthesis of Compound TC-099

[0794]

[0795] Synthesis of intermediate 3

[0796] The synthetic route is as follows:

[0797]

[0798] 1. Synthesis of Compound 2

[0799] 600 mg of 1 was weighed and dissolved in 6 mL of DMF in a 50 mL three-necked flask, and then 188 mg of A1 and 469 mg of DIPEA were added. After N2 ventilation three times, the mixture was reacted at 90°C overnight. TLC monitored the reaction and new spots were generated. Water was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and column chromatography was performed to obtain 448 mg of compound 2.

[0800] 2. Synthesis of Intermediate 3

[0801] In a 50 mL single-mouth bottle, 448 mg of compound 2 and 252 mg of DIPEA were dissolved in 5 mL of DCM, and 206 mg of A2 was dissolved in 2 mL of DCM, and then slowly added dropwise to the reaction solution. After N2 ventilation three times, the reaction was allowed to react at room temperature for 2 h. The reaction was monitored by TLC until compound 2 was no longer reduced. The reaction solution was directly decompressed and dried, and 286 mg of intermediate 3 was obtained by column chromatography.

[0802] Synthesis of compound TC-099

[0803] The synthetic route is as follows:

[0804]

[0805] 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 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 hours. The reaction was completed when TLC detected that the reaction was complete. The reaction solution was decompressed and dried, and the sample was mixed and subjected to column chromatography to obtain 190 mg of compound TC-099.

[0806] 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)

[0807] Comparative Example 2-1: DZL-1

[0808]

[0809] The synthesis method refers to Haisike WO2024083183A1

[0810] Comparative Example 2-2: DZL-2

[0811]

[0812] The synthesis method refers to T-14 in Tongyuankang WO2023088385A1

[0813] Example 3-1: Synthesis of compound TD-001

[0814]

[0815] Synthesis of intermediate compound M1

[0816]

[0817] 1. Synthesis of Compound 2

[0818] In a 250 mL three-necked flask, 10 g SM1, 10.7 g vinyl boron trifluoride, 2.9 g pd(dppf)Cl2, and 8.2 g potassium carbonate were dissolved in 50 mL 1,4-dioxane and 10 mL H2O. The mixture was heated to 100°C under N2 protection and reacted overnight. TLC monitored the reaction until it was complete. The reaction solution was cooled to room temperature and filtered to remove insoluble impurities. The filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried. The sample was directly spin-dried and subjected to column chromatography to obtain 14.4 g of compound 2. LC-MS [M+1]: 198.

[0819] 2. Synthesis of Compound 3

[0820] 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, and the mixture was heated to 100°C under N2 protection and reacted overnight. TLC showed that the raw material disappeared, and the reaction solution was cooled to room temperature, filtered to remove insoluble impurities, and the filtrate was extracted with EA after adding water. The organic phase was washed once with saturated NaCl and dried, and the sample was directly spin-dried and mixed, and 3.8 g of compound 3 was obtained by column chromatography. LC-MS [M+1]: 364.

[0821] 3. Synthesis of compound 4

[0822] In a 100 mL reactor, 3.8 g of compound 3 and 1.5 g of palladium carbon were dissolved in 35 mL of methanol, and reacted at room temperature overnight under H2 protection. TLC showed that the raw material disappeared, and the reaction solution was filtered to remove insoluble impurities. The filtrate was directly dried and mixed, and column chromatography was performed to obtain 2.9 g of compound 4. LC-MS [M+1]: 336.

[0823] 4. Synthesis of intermediate M1

[0824] 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, and the temperature was raised to 90°C under N2 protection, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until it was complete, and then quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and spin-dried. 331 mg of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 496.

[0825] Synthesis of intermediate compound M2

[0826] The synthetic route is as follows:

[0827]

[0828] 1. Synthesis of compound 2a

[0829] In a 50ml three-necked flask, 220mg of compound 1a (1.0 equivalent), 67mg of bromoethanol (1.2 equivalent), 172mg of DIPEA (3.0 equivalent) and 5ml of DMF were mixed evenly and refluxed at 90°C overnight. TLC (DCM:MEOH=10:1) was used to monitor the reaction until it was complete. The reaction solution was cooled to room temperature and diluted with EA (5ml). 15ml of ethyl acetate was used for extraction three times. The organic phases were combined and mixed and passed through a column, and 140mg of compound 2a was obtained by column chromatography.

[0830] 2. Synthesis of Compound M2

[0831] In a 50 ml single-necked bottle, 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 reacted for 16 h. The solvent was removed by rotary evaporation, and 60 mg of compound M2 was obtained by column chromatography.

[0832] Synthesis of intermediate M3

[0833] The synthetic route is as follows:

[0834]

[0835] 1. Synthesis of compound 2b

[0836] 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 evenly and protected with nitrogen. 63mg of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 equivalent) was added again, nitrogen was replaced three times, and the temperature was raised to 100°C, and the reaction was allowed to proceed overnight. TLC monitored the reaction until it was complete, filtered through a diatomaceous earth pad, and the mother liquor was collected. The mother liquor was evaporated to remove the solvent, and 30ml of water was added, and 15ml of ethyl acetate was extracted three times. The organic phases were combined and mixed, and passed through a column, and 345mg of compound 2b was obtained by column chromatography.

[0837] 2. Synthesis of compound 3b

[0838] In a 50 ml single-mouth bottle, 345 mg of compound 2b and 34.5 mg of Pd / C were added to 3.4 ml of MeOH, hydrogen was replaced three times, and the reaction was carried out at room temperature for 6 h under the protection of a hydrogen balloon. After the reaction was completed, the reaction solution was filtered to remove palladium carbon. The filtrate was evaporated to remove the solvent to obtain 345 mg of compound 3b. LC-MS [M+1]: 446.

[0839] 3. Synthesis of Compound M3

[0840] In a 50 ml single-mouth bottle, 345 mg of compound 3b and 2 ml of hydrochloric acid-tetradioxane solution were added to 3 ml of THF and reacted at room temperature for 6 h. After the reaction was complete, it was directly evaporated to dryness for subsequent reactions. LC-MS [M+1]: 346.

[0841] Synthesis of compound TD-001

[0842] The synthetic route is as follows:

[0843]

[0844] 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, and then 17.2 mg of KI and 33 mg of DIPEA were added. After N2 ventilation three times, the mixture was reacted at 75°C for 16 h. The reaction was complete when detected by TLC. The reaction solution was decompressed and dried, and then 33 mg of compound was obtained by column chromatography.

[0845] LC-MS[M+1]:867.41.

[0846] 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=7.6Hz,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).

[0847] Referring to the synthesis method of intermediate compound M2 and the synthesis method of compound TD-001, the following compounds were synthesized respectively:

[0848]

[0849] Comparative Example 3-1: Synthesis of Compound C1

[0850] The synthetic route is as follows:

[0851]

[0852] Compounds M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml NN-dimethylformamide in a 50 ml round-bottom flask, and the mixture was cooled to 0°C in an ice-water bath. NN-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added with stirring, and the mixture was reacted in an ice-water bath for 1 hour under nitrogen protection. The mixture was naturally warmed to room temperature. The reaction was complete when detected 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.

[0853] 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).

[0854] Test of compound's cell growth inhibitory activity

[0855] Test Example 1 Cell Antiproliferation Experiment

[0856] 1. Experimental materials and equipment:

[0857] H1975 has EGFR: T790M / L858R double mutation, PC-9 has EGFR exon 19 deletion, and HCC827 has 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 aminoacid mutations purchased from Kangyuan Bochuang, and Baf3-L858R-T790M-C797S (Baf3-LTC for short) is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations purchased from Kangyuan Bochuang. A549 is wild-type EGFR, purchased from Nanjing Kebai Biotechnology, and A431 is wild-type EGFR, purchased from Shanghai Xinyu Biotechnology CellCounting-Lite2.0, Trypsin EDTA, 37℃ CO2 incubator, cell counter, EnVision Serial No.1050454.

[0858] 2. Experimental preparation:

[0859] 1. 96-well plate

[0860] A) Digest the cells in the logarithmic phase with Trypsin EDTA, add culture medium to terminate the reaction, and mix with a pipette to prepare a cell suspension.

[0861] B) Use Vi-cell to measure the cell concentration and make a suspension of 15,000-25,000 cells per ml according to the experimental purpose and cell characteristics.

[0862] C) After the cell suspension is prepared, mix gently and add 100 μl to each well, so that the cell density to be tested is 1500-2500 per well.

[0863] 2. Compound treatment

[0864] Compound dilution

[0865] A) Weigh about 2 mg of the compound and calculate the required volume of DMSO according to the formula: compound mass (mg) * compound purity (%) / compound molecular weight * 1000

[0866] B) The inoculated cell culture plate is placed in an incubator and cultured for about 24 hours, and compounds with gradient concentrations are added.

[0867] C) Dilute the 10 mM compound stock solution to 50 mM with culture medium, add the 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.

[0868] D) Serial dilution: pipette 125 μl of solution from the second column and add it to the third column. Mix well. Pipet 125 μl of solution from the third column and add it to the fourth column. Repeat this operation until the tenth column.

[0869] E) Using a multi-channel pipette, 25 μl of compound was drawn from the deep-well plate and added to a 96-well culture plate, and each compound was repeated three times on the 96-well plate. Finally, a concentration gradient of 1:4 with a maximum concentration of 10,000 nM was formed on the 96-well plate.

[0870] 3. Add CTG and read the value

[0871] 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.

[0872] 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.

[0873] 4. Data Analysis

[0874] The cell viability was calculated using the following formula:

[0875] %Cell Viability=100%×(Lum_Sample-Lum_LC) / (Lum_HC-Lum_LC)

[0876] Lum_HC: 0.1% DMSO control group cell readings

[0877] Lum_Sample: Cell readout with added compound

[0878] Lum_LC: Blank medium reading

[0879] The IC50 value was obtained by curve fitting using GraphPad Prism 8 software.

[0880] As shown in Table 1, AA≤10nM; 10nM <A≤100nM;100nM<B<1000nM;C≥1000nM。

[0881] Table 1

[0882]

[0883]

[0884] 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 second-best inhibitory effect on cells containing exon 19 deletion. The inhibitory effect on wild-type EGFR is not obvious.

[0885] In addition, based on Table 1, the following conclusions are obtained:

[0886] 1) Comparison between TA-023 and TC-157 showed that the spirocyclic structure in the selection of ring B had better inhibitory activity against the L858 mutation than the piperazine ring and improved the inhibition of wild-type EGFR;

[0887] 2) Comparison of TC-225 and TA-023 shows that inhibition of mutant EGFR is reduced when the position of the spirocyclic ring is changed;

[0888] 3) Comparison of TC-213 and TC-215 with TC-157 shows that adding fluorine atoms at specific positions can increase the inhibitory effect on EGFR and reduce the inhibitory effect on wild-type EGFR;

[0889] 4) Comparison between TC-185 and TC-157 shows that the selection of wild-type EGFR can be improved when a cyclic oxygen phosphorus structure is used instead of a dimethyl phosphorus structure;

[0890] 5) Comparison between 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.

[0891] 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 has higher selectivity for wild-type EGFR.

[0892] Experimental Example 2EGFR PROTAC HTRF Experiment

[0893] 1. Instruments and reagents

[0894]

[0895]

[0896] Among them, Baf3-19del-T790M-C797S (abbreviated as Baf3-DTC) is 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 (abbreviated as Baf3-LTC) is Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Bochuang.

[0897] 2. Experimental procedures

[0898] 1) Cell preparation:

[0899]

[0900] 2) Reagent preparation:

[0901]

[0902] Dilute Eu and d2 antibody 20 times with detection buffer according to the amount of 2 μl antibody per well. Then mix the two antibodies.

[0903] 3) Detection:

[0904]

[0905]

[0906] 3. Results and calculations

[0907] Open EnVision, find the HTRF program, set up the plate, and then read the plate.

[0908] Use GraphPad Prism to generate the fitting curve, DC50 and Dmax of the compound.

[0909] 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.

[0910] Table 2

[0911]

[0912]

[0913] 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.

[0914] Pharmacokinetic studies of compounds

[0915] Test Example 3 Pharmacokinetic Test in Male SD Rats

[0916] 3.1. Experimental animals

[0917] Three healthy adult SD rats, male, 6-8 weeks old, weighing 200-300 g.

[0918] 3.2. Equipment and reagents

[0919] 3.2.1. Equipment

[0920] Analytical balance, animal weighing scale, magnetic stirrer, gavage needle, refrigerated centrifuge, single-channel manual pipette, liquid chromatography-mass spectrometry, etc.

[0921] Reagents

[0922] EDTA-Na2 anticoagulant Weigh 11.2g of EDTA-Na2, place in a reagent bottle, add 100mL of normal saline, and shake to completely dissolve. After preparation, divide into 1.5mL centrifuge tubes, each containing about 20uL, for whole blood sample collection.

[0923] 3.3. Experimental process

[0924] 3.3.1. Drug preparation

[0925] Accurately weigh about 10 mg of the sample to be tested, add 10% of the total volume of DMSO to dissolve it, then slowly add 90% of the total volume of 0.5% MC solvent while stirring, sonicate, and vortex to mix, to obtain a visually uniform solution of the preparation, with a concentration of 1 mg / mL; prepare freshly before use.

[0926] Pipette 0.2 mL of sample into a 1.5 mL centrifuge tube and store at -80°C for concentration analysis of the dosing solution.

[0927] 3.3.2 Animal preparation

[0928] The animals were kept in rat cages and fasted from the day before the experiment (for no less than 10 hours), but water was not allowed. They were weighed and marked on the tail on the day of the experiment. Blank blood was collected before administration. Blood was collected from the tail vein.

[0929] 3.3.3. Drug administration

[0930] Route of administration: oral administration (po);

[0931] Dosing concentration: 1mg / ml;

[0932] Dosage: 10 mg / kg;

[0933] Dosing volume: 10mL / kg;

[0934] Operation procedure: Use your left hand wearing a bite-proof glove to hold the rat upright, insert the gavage needle into the mouth and throat, and try to insert the needle when there is no obvious resistance, then inject the drug into the stomach.

[0935] 3.4. Sample collection

[0936] Collect 0.1-0.2 ml of whole blood from the test animals at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after administration, put them in EDTA-Na2 anticoagulant tubes, mix them by inverting them 3-4 times, centrifuge them at 4℃, 2000g for 5min to separate the upper plasma, and transfer them to -80℃ for storage for testing. Blood was collected from the tail vein.

[0937] 3.5. Sample analysis and data processing

[0938] Sample analysis

[0939] Using Shimadzu liquid phase and Triple Quad TM 6500 + AB mass spectrometry is used to establish a quantitative detection method for the test compound. The concentration of the original drug in plasma is analyzed. The analysis results are subjected to variation control using quality control samples, and the accuracy of the quality control samples should be between 80% and 120%.

[0940] Data processing

[0941] The non-compartmental model in Winnonlin Phoenix software was used to calculate the main pharmacokinetic parameters, 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.

[0942] The results are shown in Table 3.

[0943] Table 3

[0944]

[0945] It can be seen from Table 3 that the compounds of the present invention have good pharmacokinetic effects.

[0946] Test Example 4: Pharmacokinetics test in CD-1 mice

[0947] 4.1. Purpose of the experiment

[0948] After a single oral administration of the test substance to CD-1 male mice, plasma of the CD-1 mice was collected and analyzed to calculate the pharmacokinetic parameters.

[0949] 4.2. Test and Standard Product Information

[0950] The free base conversion factor calculation formula is: conversion factor CF = (MW / FW) * purity.

[0951] 4.3. Preparation

[0952] The solvent was 5% DMSO + 10% Solutol HS-15 + 85% Saline.

[0953] 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.

[0954] Before administration, keep 2 samples of the preparation and the remaining preparation after administration, and store them at 2-8°C until mailing.

[0955] 4.4. Experimental animals

[0956] The experimental animals were kept in the SPF animal room of Suzhou Xihua New Drug Development Co., Ltd. (Use Permit No.: SYXK(Su)2021-0019). The animals were fed normally for at least 3 days after purchase before the experiment, and each mouse was marked with a tail number. The animals in the oral administration group were fasted overnight the day before administration, and feeding was resumed 4 hours after administration, with free access to water. The sources and numbers of animals used in this experiment are shown in Table 4.

[0957] Table 4 Source and number of experimental animals

[0958]

[0959] Experimental design

[0960] 1) The subjects were free to drink water before and after administration;

[0961] 2) All experiments were conducted according to the actual body weight of the animals;

[0962] 3) Administration: Oral administration (PO), fasting overnight before administration.

[0963] Before administration, check the state of the drug preparation, ensure the uniformity of the preparation by vortexing, stirring or shaking, and calculate the theoretical administration volume for each CD-1 mouse in each group according to the following formula.

[0964]

[0965] 4.6. Sample collection and processing

[0966] The sample collection information is shown in Table 5.

[0967] Table 5 Sample collection information

[0968]

[0969] Remark:

[0970] 1) The blood collection time window for blood collection points 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 samples are sent for testing.

[0971] 40 μL of whole blood was collected from the submandibular vein of mice at each time point in Table 5, placed in a test tube containing anticoagulant EDTA-K2 (15% EDTA-K2 solution), stored on wet ice, and centrifuged within 45 minutes (1,500 g, 2-8°C, centrifuged for 10 minutes) to obtain plasma. The plasma was stored in a pre-cooled centrifuge tube, quickly frozen in dry ice, and then stored in an ultra-low temperature refrigerator at -60°C or lower until shipped.

[0972] 4.7 Experimental observations

[0973] During the experiment, any abnormal reactions of the animals were recorded in detail.

[0974] 4.8. Sample analysis and data processing

[0975] Sample analysis

[0976] The quantitative detection method of the test compound was established using Shimadzu liquid chromatography and Triple Quad TM 6500+AB mass spectrometry. The concentration of the original drug in plasma was analyzed. The analysis results were controlled for variation using quality control samples, and the accuracy of the quality control samples should be between 80% and 120%.

[0977] Data processing

[0978] The non-compartmental model in Winnonlin Phoenix software was used to calculate the main pharmacokinetic parameters, 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 reach maximum plasma concentration (Tmax).

[0979] The results are shown in Table 6.

[0980] Table 6

[0981]

[0982] It can be seen from Table 6 that the compound of the present invention has excellent pharmacokinetic effect. Compared with the control example 1-1, it has a higher exposure amount and better pharmacokinetic effect.

[0983] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

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, hydroxy 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 is selected from the group consisting of a substituted or unsubstituted 6-7 membered heterocyclyl, a substituted or unsubstituted 7-12 membered heterospirocyclyl, a 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 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.

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