Compounds for EGFR protein degradation and their uses

Abstract

The present invention relates to compounds for degrading EGFR protein and their uses. Specifically, the compounds of the present invention have the structure shown in Formula III, wherein the definitions of each group and substituent are as described in the specification. The present invention also discloses the preparation methods of the compounds and their uses in preventing and / or treating 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 the prevention and / or treatment of EGFR-related diseases.

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

[0009]

[0010] wherein,

[0011] X3 is selected from nothing, NH, NR;

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

[0013] Each R is independently selected from C 1-6 alkyl, halo 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 heteroarylene group, a substituted or unsubstituted 7-9 membered heterospiro group; said substitution is that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: H, halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl;

[0017] Ring A is selected from the group consisting of: a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted 6-10 membered heteroaryl; said substitution means that 0-1 hydrogen on the group is substituted by R6, and m hydrogens are substituted by R7; m is 0, 1, or 2;

[0018] wherein,

[0019] R6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 hydroxyalkyl, halo 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- to 7-membered heterocyclic group -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 commonly attached form a 5- to 7-membered heterocycle;

[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, halo 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- to 6-membered heteroalkyl; wherein the heteroalkyl contains at least one heteroatom selected from the group consisting of O, N, and S, and wherein the substitution means that one or more hydrogens on the group are replaced by a group selected from the group consisting of cyano, nitro, hydroxy, amino, 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 R5s together with the carbon atom to which they are commonly attached form a C 3-6 membered cycloalkyl;

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

[0028] In another preferred embodiment, R6 is located at the ortho position of the attachment site.

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

[0030] wherein R6, R7, 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 group consisting of:

[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, hydroxy, cyano, C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo-C 1-6 alkyl, C 1-6 hydroxyalkyl.

[0033] In another preferred example, ring B is substituted with substituents selected from the group consisting of: H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0034] In another preferred example, R6 is selected from the group consisting of: C 1-6 alkyl, C 1-6 hydroxyalkyl, -P(O)RaRb, -C(O)NHR, -C(O)NRaRb, -OC(O)NHR, -OC(O)NRaRb, -S(O)2R, -NR-S(O)2R, -NR-C(O)-OR, -NH-C(O)-OR;

[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 commonly attached form a 5-membered heterocycle.

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

[0037]

[0038] wherein,

[0039] X1 is selected from CH, N;

[0040] X2 is selected from NR;

[0041] R is selected from C 1-3 alkyl, halo-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, and wherein the substitution means that one or more hydrogens on the group are substituted with a group selected from the group consisting of: cyano, nitro, hydroxy, amino, 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 R5s together with the carbon atom to which they are commonly attached form a C 3-4 cycloalkyl;

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

[0049] R7 is selected from the group consisting of: H, C 3-6 cycloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy;

[0050] R8 is selected from the group consisting of: C 1-4 alkyl, halo C 1-4 alkyl;

[0051] m is 0, 1 or 2.

[0052] In another preferred embodiment, R4 and R5 are not both 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, Br.

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

[0058] In a second aspect of the present invention, there is provided 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] wherein,

[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 group consisting of: C 1-6 alkyl, C 6-10 aryl;

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

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

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

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

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

[0069] Ring B is selected from the group consisting of: substituted or unsubstituted 6- to 7-membered hetero monocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 7- to 9-membered hetero bridged cyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 7- to 10-membered hetero spirocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S; the substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0070] Ring C is selected from the group consisting of: substituted or unsubstituted 6- to 7-membered hetero monocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 7- to 9-membered hetero spirocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 4- to 10-membered hetero bridged cyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 5- to 7-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, or S; the substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, amino, nitro, hydroxy, cyano, C 1-6 alkyl, halo 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- to 10-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O, or S; the substitution means that 1 hydrogen on the group is substituted by R6, and m hydrogens are substituted by R7;

[0072] R6 is selected from the group consisting of: 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, halo-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, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, -(C=O)-O-C 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 group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl; or R8, together with R' and the atoms to which it is attached, forms a 5- to 6-membered heterocyclic group containing 1 O;

[0082] L is selected from the group consisting of:

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

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

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

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

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

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

[0089] In another preferred example, X3 is selected from the group consisting of: none, NH, NR, O.

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

[0091] In another preferred example, X2 is selected from the group consisting of: NR, O, S.

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

[0093] In another preferred example, X1 is selected from the group consisting of: CH, N.

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

[0095] In another preferred example, X 11 is selected from the group consisting of: CH, N.

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

[0097] In another preferred example, X4 is selected from the group consisting of: N, CR'.

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

[0099] In another preferred example, X5 is selected from the group consisting of: CH, N, C.

[0100] In another preferred example, X5 is selected from the group consisting of: CH, C.

[0101] In another preferred example, X 51 is selected from the group consisting of: C-(OH), N, C.

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

[0103] In another preferred example, ring A is

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

[0105] In another preferred example, R6 is selected from the group consisting of: C 1-6 alkyl, C substituted with hydroxyl 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 group consisting of: -P(O)RaRb, -C(O)NRaRb.

[0108] In another preferred embodiment, Ra and Rb are each independently selected from the group consisting of: H, C 1-6 alkyl, C 3-6 cycloalkyl.

[0109] In another preferred embodiment, Ra is selected from the group consisting of: 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 group consisting of: H, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, -(C═O)-O-C 1-6 alkyl, -(C═O)-NH-C 1-6 alkyl.

[0112] In another preferred embodiment, R2 is selected from the group consisting of: C 1-6 alkyl, halo-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 group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl; or R8, together with R' and the atoms connected thereto, forms a 5- to 6-membered heterocyclic group containing 1 O.

[0115] In another preferred embodiment, R8 is selected from the group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl.

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

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

[0118] Among them, the said substitution means that one or more hydrogens on the group are substituted by substituents selected from the following group: halogen, amino, nitro, hydroxyl, cyano, C 1-6 alkyl, halo-C 1-6 alkyl, hydroxyl-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0119] In another preferred example, the ring C is selected from the following group:

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

[0121] In another preferred example, the said compound is selected from the following group: Compound of formula II’, Compound of formula III’, Compound of formula IV’:

[0122]

[0123]

[0124] Among them,

[0125] X1 is selected from the following group: CH, N;

[0126] X2 is NR;

[0127] R is C 1-3 alkyl;

[0128] X3 is selected from the following group: none, NH;

[0129] R1 is halogen;

[0130] R2 is selected from the following group: H, halogen, C 1-6 alkyl, halo-C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy, C 3-6 cycloalkyl, -(C=O)-O-C 1-6 alkyl, -(C=O)-NH-C 1-6 alkyl;

[0131] R3 is halogen;

[0132] R 41 is selected from the following group: 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 group consisting of: H, C 3-6 cycloalkyl, halogen, C 1-6 alkyl, C 1-6 alkoxy;

[0139] R8 is selected from the group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl;

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

[0141] In a 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] wherein,

[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 nothing (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, halo-C 1-6 alkyl, halo-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 commonly attached together form Cy1, where Cy1 is selected from the group consisting of: saturated or partially unsaturated 4- to 7-membered rings containing P═O, said rings containing, in addition to P, 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and said rings are optionally substituted by one or more substituents R a substituted; or

[0151] R7, R8 are each independently selected from the group consisting of: C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl;

[0152] R a is 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- to 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 , where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by R d substituted;

[0153] R b , R c and R d are each independently selected from the group consisting of: hydrogen, hydroxy, 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, halo C 1-6 alkyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-8 heterocycloalkyl, -(C═O)-O-C 1-6 alkyl, -(C═O)-NH-C 1-6 alkyl, halogen, -(CH2)p -C 1-4 alkoxy, -(CH2) p -halo C 1-4 alkoxy, -(CH2) p -CN, C 1-6 alkyl-substituted or unsubstituted 5- or 6-membered heteroaryl and 2- to 6-membered heteroalkyl containing 1 to 3 heteroatoms independently selected from N, O, or S; wherein said heteroalkyl or heterocycloalkyl contains one or more heteroatoms independently selected from the group consisting of O, N, and S; p is 0, 1, 2, or 3;

[0156] R3 is selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxy, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or C 1-4 hydroxyalkyl;

[0157] R4 is selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxy, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or C 1-4 hydroxyalkyl;

[0158] R5 is selected from the group consisting of: H, halogen, cyano, amino, nitro, hydroxy, C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy, halo C 1-4 alkoxy or C 1-4 hydroxyalkyl;

[0159] Alternatively, R4 and R5 form a C3-6 carbocycle or a 3- to 7-membered heterocycle, wherein the heteroatoms in said heterocycle are selected from O, N, or S;

[0160] R6 is selected from the group consisting of: C 1-6 alkyl, halo C 1-6 alkyl, or C 1-6 hydroxyalkyl; or, X4 is CR, and the R of X4 is linked to R6 to form a saturated or partially saturated 5- or 6-membered heterocyclic group containing 1 O;

[0161] Ring B is selected from the group consisting of: substituted or unsubstituted 6- or 7-membered hetero-subcyclic groups, substituted or unsubstituted 7- to 12-membered hetero-spirocyclic groups, substituted or unsubstituted 7- to 12-membered hetero-bridged cyclic groups; said substitution means that one or more hydrogens on the group are substituted with substituents selected from the group consisting of: H, D, halogen, amino, oxo(=O), nitro, hydroxy, cyano, C 1-6alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, or any two hydrogen atoms are linked to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5 (such as compounds TB-081, TB-056, etc.);

[0162] cyclo C selected from the group consisting of: substituted or unsubstituted 6- to 7-membered heteroarylene groups, substituted or unsubstituted 5- to 6-membered heteroarylene groups, or substituted or unsubstituted 7- to 12-membered heterospiro groups; said substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: H, halogen, amino, oxo(=O), nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, or any two hydrogen atoms are linked to form a bond or -(CH2) q -, where q is 1, 2, 3, 4, or 5;

[0163] wherein each of the heteroarylene group, heteroarylene group, heterospiro group, and heterobridged ring group independently contains 1-3 heteroatoms selected from N, S, and O.

[0164] In another preferred embodiment, R is selected from the group consisting of: C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo 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 is selected from the group consisting of: hydrogen, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic group, phenyl, 5- to 6-membered heteroaryl, -CN, -OR b 、-COR b 、-COOR b 、CONR b R c 、-NR b R c 、-NR b CORc or -NR b COOR c wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl are optionally substituted by R d substituted;

[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 group consisting of: C 1-6 alkyl, halo C 1-6 alkyl.

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

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

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

[0172] In another preferred embodiment, ring B is selected from the group consisting of: substituted or unsubstituted 6-7 membered hetero-subcyclic group, or substituted or unsubstituted 7-10 membered hetero-spirocyclic group; preferably, ring B is a substituted or unsubstituted group selected from the group consisting of: wherein the substitution is that one or more hydrogens on the group are substituted by substituents 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, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, or any two hydrogen atoms are connected to form a bond or -(CH2) q -, wherein 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: 6-7 membered hetero-subcyclic group, 5-6 membered hetero-aryl group, or 7-10 membered hetero-spirocyclic group; preferably, ring C is a substituted or unsubstituted group selected from the following group: wherein said substitution is that one or more hydrogens on the group are substituted by substituents selected from the following group: H, halogen, amino, oxo(=O), nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, or any two hydrogen atoms are connected to form a bond or -(CH2) q -, wherein 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 example, the compound has the 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 example, the compound has the 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, halo 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 -, wherein q is 1, 2, 3, 4, or 5;

[0183] or two R' or two R” attached to the same carbon atom can together with the attached carbon atom form a 3-6 membered saturated carbocyclic ring;

[0184] m, 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, selected from the group consisting of:

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

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

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

[0190]

[0191] wherein,

[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 the structure shown in Formula 4:

[0194]

[0195] wherein,

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

[0197] In another preferred embodiment, ring C is a substituted or unsubstituted group selected from the group consisting of: wherein, the substitution is that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: H, halogen, amino, oxo (=O), nitro, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halo C 1-6 alkyl, C 1-6 hydroxyalkyl, or any two hydrogen atoms are connected to form a bond or -(CH2) q -, wherein, 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 group consisting of: CH3, phenyl, isopropyl, cyclopropyl.

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

[0200] In another preferred example, L is selected from the group consisting of: ethylene,

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

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

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

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

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

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

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

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

[0209] In the fourth aspect of the present invention, there is provided a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug thereof, said compound being 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 a fifth aspect of the present invention, there is provided a pharmaceutical composition 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 an injection, tablet, capsule, pill, suspension or emulsion; preferably an injection.

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

[0244] (a1) A first active ingredient: a therapeutically effective amount of the compound described in 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, telithromycin, josamycin, IPI-504, NVP-AUY922; and

[0246] (b) A pharmaceutically acceptable carrier.

[0247] In a 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 uses selected from the group consisting of:

[0248] 1) Preparing a drug for regulating abnormal EGFR kinase activity;

[0249] 2) Preparing a drug for preventing and / or treating diseases related to abnormal or mutated EGFR kinase activity (preferably, diseases related to EGFR drug-resistant mutations); and / or

[0250] 3) Preparing a drug for degrading EGFR protein.

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

[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 mutations are selected from the group consisting of EGFRT790M, EGFRC797S, DEL19, L858R, DEL19 / T790M, DEL10 / T790M / C797S, L858R / T790M / C797S.

[0254] In another preferred embodiment, the diseases related to abnormal or mutated EGFR kinase activity are selected from the group consisting of inflammation, cancer, cardiovascular diseases, infections, immune diseases, metabolic diseases, or combinations thereof.

[0255] In another preferred embodiment, the cancer is selected from the group consisting of: 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 having an EGFR mutation selected from the group consisting of: T790M / L858R, T790M / L858R / C797S, L858R, L858R / C797S.

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

[0258] 1) Determining the EGFR kinase activation mutation status of a subject in need;

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

[0260] In another preferred embodiment, the "determining the EGFR activation mutation status of the patient" is determined by cobas EGFR mutation test v2.

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

[0262] In a ninth aspect of the present invention, there is provided a method for preventing and / or treating EGFR kinase activity abnormality or mutation-related diseases, by administering to a subject in need 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.

[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 technical features of the present invention and the technical features specifically described hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated one by one here. Detailed Embodiments

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

[0267] The term

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

[0269] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is 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-chain or branched-chain saturated hydrocarbon group containing 1 to 12 carbon atoms composed only of carbon and hydrogen atoms. Alkyl is preferably a C1-C6 alkyl (i.e., containing 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. In the present application, alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position. "Halogenated alkyl" refers to an alkyl as defined herein in which one or more hydrogens are replaced by the same or different halogens. Examples of halogenated alkyls include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

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

[0272] "Alkoxy (alone or as part of another group)" refers to an alkyl group to which an oxygen group is attached, having an alkyl O- structure, where the alkyl has the definition as described above. Preferably, the alkoxy is a C1-C6 alkoxy. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Halogenated alkoxy" refers to a group of the formula -OR, where R is a halogenated alkyl group as defined herein. Examples of halogenated alkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[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. Alkenyls include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc. In the present invention, alkenyls include substituted alkenyls.

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

[0275] "Alkynyl (alone or as part of another group)" refers to a straight-chain 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 having 2, 3, 4, 5, or 6 carbon atoms. Alkynyls include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple-bond carbons can optionally be the attachment point of an alkynyl substituent. In the present invention, alkynyls also include substituted alkynyls.

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

[0277] "Cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of a single- or bicyclic ring, having 3 - 12, preferably 3 - 10, more preferably 3 - 8 ring atoms. Cycloalkyl can optionally be substituted by one or more substituents, where each substituent is independently a hydroxyl group, alkyl group, alkoxy group, halogen, haloalkyl group, amino group, monoalkylamino group, or dialkylamino group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

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

[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, containing at least 1 aromatic ring having 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 should be on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinazolinyl, naphthyridinyl, pteridinyl, carbazolyl, azo yl, diazo yl, acridinyl, etc. Sub-heteroaryl refers to a heteroaryl having two attachment sites.

[0280] "Heterocyclic system" refers to monocyclic, bicyclic and polycyclic systems in which at least one ring is saturated or partially unsaturated (but not aromatic) and the ring contains at least one heteroatom. The heterocyclic system may be attached to a side group at any heteroatom or carbon atom, which results in a stable structure and any ring atom may optionally be substituted.

[0281] "Heterocyclic group" refers to a monovalent group of a heterocyclic system, usually a stable monocyclic ring (such as 3-8 membered rings, i.e., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered or 8-membered), or a bicyclic ring (such as 5-12 membered rings, i.e., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered), or a polycyclic ring (such as 7-14 membered rings, i.e., 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered or 14-membered), including fused rings, spiro rings 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 heterocyclic groups include the following ring systems, where (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, pyrroline, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl and quinuclidinyl; (2) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is an aromatic carbocyclic ring, for example, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring is non-aromatic and contains a heteroatom and at least one other ring is aromatic and contains a heteroatom, for example, 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-phthalazine. Subheterocyclic group refers to a heterocyclic group having two attachment sites. In the present invention, preferably, the subheterocyclic group is bicyclic, where one ring is a heteroaryl and is attached to other parts in the general formula through the heteroaryl. In the present invention, preferably, the subheterocyclic group is a 5-6 membered monocyclic subheterocyclic group or an 8-10 membered bicyclic subheterocyclic group.

[0282] "Heterocyclic group alkyl" refers to an alkyl group substituted by a heterocyclic group, where the definitions of the heterocyclic group and the alkyl group are as described above.

[0283] When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, for example, alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclic group corresponds to subheterocyclic group, alkoxy corresponds to alkoxy, etc.

[0284] In the present invention, each of the above-mentioned alkyl, alkoxy, cycloalkyl, heteroalkyl, aryl, heteroaryl, cycloheteroalkyl, alkenyl, alkyne, heterocycle, heterocyclic group, etc. can 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, heterocycle or aromatic ring, R b , R c and R d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b and R c together with the N atom may form a heterocycle; R e may 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, may be optionally substituted. The substituents include, for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1-C6 ureido group, etc.

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

[0287] "Nitro" refers to -NO2.

[0288] "Hydroxyl" refers to -OH.

[0289] "Amino" refers to -NH2 or RNH-, where R is a keto carbonyl group, sulfonyl group, sulfonamide group, R a -C(=O)-, R a R b N-C(=O)-, etc., where R a and R b are alkyl, cycloalkyl, aryl or heteroaryl, etc.

[0290] "Halogen (halo)" refers to any halogen group, for example, -F, -Cl, -Br or -I.

[0291] "Deuterated compound" refers to a compound obtained by replacing one hydrogen atom (H) or multiple hydrogen atoms (H) in a compound with deuterium atoms (D).

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

[0293] Compound 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] Among them, 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 the 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 with an acid or a base that is suitable for use as a drug. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts is the salts formed by the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, 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, naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid.

[0299] Another preferred class of salts is the salts formed by the compounds of the present invention with bases, such as alkali metal salts (such as sodium salts or potassium salts), alkaline earth metal salts (such as magnesium salts or calcium salts), ammonium salts (such as lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed by morpholine, piperazine, and lysine, respectively.

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

[0301] In addition, the compounds of the present invention also include prodrugs of the compounds represented by Formula I. The term "prodrug" includes those that may be biologically active or inactive per se, and when administered by an appropriate method, they are metabolized or undergo a chemical reaction in the human body to be converted into a class of compounds of Formula I, or a salt or solution composed of a compound of Formula I. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc. of the compounds.

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

[0303] Stereoisomers of all compounds (e.g., those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are within the scope contemplated by the present invention. The individual stereoisomers of the compounds in the present invention may not coexist with other isomers (e.g., have special activities as a pure or substantially pure optical isomer), or may also be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a part thereof. The chiral centers of the present invention have two configurations, S or R, as defined by the recommendations of the International Union of Pure and Applied Chemistry (IUPAC) in 1974. The racemic form can be resolved by physical methods, such as fractional crystallization, or by separation and crystallization after derivatization into diastereoisomers, or by chiral column chromatography. The individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to traditional methods, such as recrystallization after salification with an optically active acid.

[0304] The compounds in the present invention, obtained by preparation, separation and purification in sequence, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% (the "very pure" compounds), and are listed in the description in the text. Such "very pure" compounds of the present invention are also part of the present invention here.

[0305] All configurational isomers of the compounds of the present invention are within the covered scope, whether in the form of mixtures, pure or very pure. The definition of the compounds in the present invention includes both cis (Z) and trans (E) alkene isomers, as well as cis and trans isomers of carbocycles and heterocycles.

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

[0307] The definitions of specific functional groups and chemical terms are introduced in detail as follows. For the present invention, chemical elements are consistent with those defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. The definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry and specific functional groups and reactivity are also described in "Organic Chemistry", Thomas Sorrell, University ScienceBooks, Sausalito: 1999, the entire content of which is incorporated by reference.

[0308] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all such compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and their mixtures are included within the scope of the present invention.

[0309] According to the present invention, the ratio of isomers in a mixture of isomers can be diverse. For example, in a mixture of only two isomers, the following combinations are possible: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios that are readily understood by those of ordinary skill in the art, as well as 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, which are equivalent to the original compounds disclosed herein. However, in practice, substitution of one or more atoms with atoms having a different atomic weight or mass number typically occurs. Examples of isotopes that can be incorporated into 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 Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, that contain one or more of the aforementioned isotopes or other isotopic atoms are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 C radioactive isotopes, are also included and are useful in tissue distribution studies of drugs and substrates. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are relatively easy to prepare and detect and are preferred isotopes. Additionally, heavier isotope substitutions such as deuterium, i.e., 2H has advantages in certain therapies due to its good metabolic stability, such as increasing the half-life in vivo or reducing the dosage. Therefore, it can be preferentially considered in certain cases. Isotopically labeled compounds can be prepared by general methods, by replacing non-isotopic reagents with readily available isotopic labeling reagents, using the procedures disclosed in the examples.

[0311] If the synthesis of a specific enantiomer of a 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 is separated, and then the chiral auxiliary is removed to obtain the pure enantiomer. Additionally, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed into diastereomeric salts 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 is obtained.

[0312] As described herein, the compounds in the present invention can be taken with any number of substituents or functional groups to expand their scope of inclusion. Generally, the term "substituted", whether it appears before or after the term "optional", in the present invention's formulation includes the general formula of substituents, which means replacing a hydrogen radical with a specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, each position of the substituent can be the same or different. The term "substituted" as used herein includes all substitutions allowed for organic compounds. Broadly speaking, allowed substituents include acyclic, cyclic, branched, unbranched, carbocyclic, and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, a heteroatom such as nitrogen can have a hydrogen substituent or any allowed organic compound as described above to supplement its valence. Additionally, the present invention is not intended to limit the allowed substituted organic compounds in any way. The present invention believes that combinations of substituents and variable groups are good for the treatment of diseases in the form of stable compounds. Here, the term "stable" refers to a compound that is stable enough to maintain the integrity of the compound structure for a sufficient period of time for detection, preferably effective for a sufficient period of time, and is used herein for the above purposes.

[0313] Metabolites of the compounds and their pharmaceutically acceptable salts involved in this application, as well as prodrugs that can be converted in vivo into the structures of the compounds and their pharmaceutically acceptable salts involved in this application, are also included in the claims of this application.

[0314] It should be understood that the specific methods for preparing the compounds of formula I of the present invention are specifically described in the embodiments 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 synthesis 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 pertains.

[0315] Typically, raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased through commercial channels without special instructions.

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

[0317] Pharmaceutical compositions and administration methods

[0318] The present invention also provides a pharmaceutical composition comprising the said compound, or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, isotope or prodrug, and a pharmaceutically acceptable carrier.

[0319] Due to the excellent anti-tumor activity of the compounds of the present invention, 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 for the treatment, prevention and alleviation of diseases related to tumors.

[0320] The pharmaceutical composition of the present invention comprises the compound of the present invention or its pharmacologically acceptable salt and a pharmacologically acceptable excipient or carrier within a safe and effective amount range. The "safe and effective amount" herein refers to: the amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1 - 2000 mg of the compound of the present invention per dose, more preferably, it contains 10 - 1000 mg of the compound of the present invention per dose. Preferably, the said "one dose" is a capsule or a 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" herein 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 are 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), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0322] The said pharmaceutical composition is an injection, capsule, tablet, pill, powder or granule.

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

[0324] The dosage forms of the pharmaceutical compositions of the present invention include (but are not limited to): injections, tablets, capsules, aerosols, suppositories, membranes, dripping pills, external rubbing agents, controlled release or sustained release or nano preparations.

[0325] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier) such as sodium citrate or calcium phosphate dibasic, or admixed with the following components: (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxypropylmethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants such as glycerol; (d) disintegrants such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizing agents such as paraffin wax; (f) absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

[0326] Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared with coatings and shell materials such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a manner such that release occurs in a portion of the digestive tract. Examples of embedding components that can be used are polymeric materials and wax materials. If necessary, the active compound can also be in the form of microcapsules with one or more of the above 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 forms may contain inert diluents conventionally used in the art such as water or other solvents, solubilizing agents and emulsifying agents, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3 - butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0328] In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances.

[0329] In addition to the active compound, the suspension may contain suspending agents, such as ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures of these substances, etc.

[0330] Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous 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 of the compounds of the present invention for topical administration 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, if necessary.

[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 administered alone, or in combination with other treatment means or therapeutic drugs.

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

[0335] Drugs or active ingredients that can be used in combination with the compounds 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, tylosin, spiramycin, IPI-504, 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 in need of treatment (such as a human or a mouse), and the dosage during administration is the effective dosage considered pharmaceutically. For a person weighing 60 kg, the daily dosage is usually 1 - 2000 mg, preferably 50 - 1000 mg. Of course, the specific dosage should also consider factors such as the administration route and the patient's health condition, which are all within the scope of the skills of a skilled physician.

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

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

[0339] (2) The compound of the present invention has excellent inhibitory and / or therapeutic effects on EGFR-related diseases, especially diseases with EGFR drug-resistant mutations, and the diseases include but are not limited to the diseases selected from the following group: H1975 (T790M / L858R), HCC827 (19DEL), PC-9 (19DEL);

[0340] (3) The compound of the present invention has excellent pharmacokinetic performance;

[0341] (4) The compound of the present invention is applicable to the prevention and / or treatment of diseases selected from the following group: EGFR-sensitive mutant cancers, diseases with secondary drug resistance in current EGFR treatments;

[0342] (5) The compound of the present invention has excellent safety;

[0343] (6) The compound of the present invention has excellent degradation selectivity for wild-type EGFR and mutant EGFR proteins, and has very good degradation efficiency for mutant EGFR proteins.

[0344] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

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

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

[0347] Synthesis of Intermediate Compound M1

[0348]

[0349] 1. Synthesis of Compound 2

[0350] Dissolve 10 g of SM1, 10.7 g of boron trifluoride, 2.9 g of pd(dppf)Cl2, and 8.2 g of potassium carbonate in 50 mL of 1,4-dioxane and 10 mL of H2O in a 250 mL three-necked flask. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction. Add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl solution and then dry it. Directly evaporate to dryness and mix with silica gel. Purify by column chromatography to obtain 14.4 g of Compound 2. LC-MS [M+1]: 198.

[0351] 2. Synthesis of Compound 3

[0352] Dissolve 2.7 g of Compound 2, 4.3 g of 1-Boc piperazine, and 9.4 g of potassium carbonate in 27 mL of DMAC in a 100 mL three-necked flask. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until the raw materials disappear. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction. Add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl solution and then dry it. Directly evaporate to dryness and mix with silica gel. Purify by column chromatography to obtain 3.8 g of Compound 3. LC-MS [M+1]: 364.

[0353] 3. Synthesis of Compound 4

[0354] Dissolve 3.8 g of Compound 3 and 1.5 g of palladium carbon in 35 mL of methanol in a 100 mL autoclave. After protecting with H2 gas, react at room temperature overnight. Monitor the reaction by TLC until the raw materials disappear. Filter off the insoluble impurities from the reaction solution by suction. Directly evaporate the filtrate to dryness and mix with silica gel. Purify by column chromatography to obtain 2.9 g of Compound 4. LC-MS [M+1]: 336.

[0355] 4. Synthesis of Intermediate M1

[0356] Dissolve 300 mg of Compound 4, 265 mg of SM2, and 220 mg of p-toluenesulfonic acid monohydrate in 3 mL of isopropanol in a 100 ml reaction tube. After protecting with N2 gas, heat the mixture to 90 °C and react overnight. Monitor the reaction by TLC until it is complete. Quench with a small amount of saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography to obtain 331 mg of Intermediate M1. LC-MS [M+1]: 496.

[0357] Synthesis of Intermediate Compound M2

[0358]

[0359] Dissolve 8.3 g of SM1 in 100 mL of dichloromethane in a 250 mL three-necked flask. After protecting with N2 gas, add triethylamine. Cool the temperature to 0 °C in an ice bath, slowly add TF2O dropwise, and react overnight at room temperature. Monitor the reaction by TLC until it is complete. Add water to the reaction solution and extract with EA. Wash the organic phase once with saturated NaCl, dry it, evaporate to dryness and mix with silica gel, and obtain 2 g of intermediate M2 by column chromatography.

[0360] Synthesis of Intermediate Compound M3

[0361]

[0362] 1. Synthesis of Compound 2

[0363] Dissolve 2 g of SM1, 2.2 g of bis(pinacolato)diboron, 2.4 g of pd(dppf)Cl2, and 1.7 g of potassium acetate in 30 mL of 1,4-dioxane in a 100 mL three-necked flask. After protecting with N2 gas, heat the temperature to 85 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction filtration. Add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl, dry it, directly evaporate to dryness and mix with silica gel, and obtain 2 g of Compound 2 by column chromatography. LC-MS [M+1]: 389.

[0364] 2. Synthesis of Compound 3

[0365] Dissolve 2 g of Compound 2, 2 g of intermediate M2, 1.5 g of sodium carbonate, and 376 mg of pd(dppf)Cl2 in 40 mL of 1,4-dioxane and 10 mL of H2O in a 250 mL three-necked flask. After protecting with N2 gas, heat the temperature to 55 °C and react for 2 h. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction filtration. Add water to the filtrate and extract with dichloromethane. Wash the organic phase once with saturated NaCl, dry it, evaporate to dryness and mix with silica gel, and obtain 1.8 g of Compound 3 by column chromatography. LC-MS [M+1]: 480.

[0366] 3. Synthesis of Compound 4

[0367] Dissolve 1.8 g of Compound 3 in 18 mL of ethyl acetate in a 100 mL single-necked flask, add 1,4-dioxane hydrochloride, and react overnight at room temperature. TLC shows that the raw materials disappear. Filter the reaction solution by suction filtration to obtain 1 g of filter cake, which is Compound 4. LC-MS [M+1]: 380.

[0368] 4. Synthesis of Compound 5

[0369] Dissolve 1 g of Compound 4 in 10 mL of DMF in a 100 mL three-necked flask. After protecting with N2 gas, add 2 mL of N,N-diisopropylethylamine. Stir for 10 min under an ice bath, then add 0.4 mL of tert-butyl bromoacetate. React at room temperature overnight. Monitor the reaction by TLC until completion. Add water to the reaction solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, rotary evaporate, and perform column chromatography to obtain 1.5 g of Compound 5. LC-MS [M+1]: 494.

[0370] 5. Synthesis of Compound 6

[0371] Dissolve 1.5 g of Compound 5 and 228 mg of palladium carbon in 30 mL of methanol in a 100 mL autoclave. After protecting with H2 gas, react at room temperature overnight. TLC shows that the raw materials disappear. Filter the reaction solution to remove insoluble impurities, directly rotary evaporate the filtrate and mix the sample, and perform column chromatography to obtain 200 mg of Compound 6. LC-MS [M+1]: 496.

[0372] 6. Synthesis of Intermediate M3

[0373] Add 200 mg of Compound 6 to a 100 mL reaction tube, dissolve it in 1 mL of dichloromethane, add 0.2 mL of trifluoroacetic acid, and react at room temperature overnight. TLC shows that the raw materials disappear. Concentrate the reaction solution to remove the solvent to obtain 283 mg of Intermediate M3. LC-MS [M+1]: 440.

[0374] Synthesis of Compound TA-003

[0375]

[0376] Dissolve 98 mg of Compound M1 and 139 mg of Compound M3 in 1 mL of NN-dimethylformamide in a 100 mL reaction tube. Cool to 0 °C in an ice-water bath, add N,N-diisopropylethylamine and HATU under stirring, react in an ice-water bath for 1 hour under nitrogen protection, naturally warm to room temperature, and react overnight. Detect the completion of the reaction by TLC, extract with dichloromethane and water, dry the organic phase, and perform column chromatography to obtain 80 mg of Compound TA-003. LC-MS [M+1]: 917.8.

[0377] 11H NMR (400 MHz, DMSO) δ 11.62 (s, 1H), 10.60 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.57 (d, J = 7.0 Hz, 1H), 8.23 (s, 1H), 8.14 (s, 1H), 7.69 (t, J = 5.8 Hz, 2H), 7.50 (s, 1H), 7.43 (d, J = 10.4 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.82 (s, 1H), 3.99 (s, 3H), 3.91 (t, J = 6.7 Hz, 2H), 3.75 (s, 6H), 3.59 (s, 2H), 3.49 (d, J = 15.4 Hz, 3H), 3.06 (d, J = 10.3 Hz, 1H), 2.92 (s, 1H), 2.89 (s, 1H), 2.83 (d, J = 5.1 Hz, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.75 (dd, J = 12.1, 5.6 Hz, 3H), 2.63 (dd, J = 14.7, 7.3 Hz, 2H), 2.58–2.53 (m, 1H), 2.39 (d, J = 12.0 Hz, 1H), 1.86 (d, J = 11.9 Hz, 1H), 1.10 (t, J = 7.4 Hz, 3H).

[0378] Referring to the synthesis methods of intermediate compound M1 and 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] Dissolve 500 mg of (2 - aminophenyl)dimethylphosphine oxide in 10 mL of isopropanol in a 100 mL single - necked flask. Sequentially add 0.7 mL of 2,4,5 - trichloropyrimidine and 2.9 mL of DIPEA. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Directly evaporate the reaction solution to dryness, mix the sample, and perform column chromatography to obtain 1 g of intermediate M1. 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 of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and insoluble impurities were removed by suction filtration. The filtrate was diluted with water and extracted with EA. The organic phase was washed once with saturated NaCl solution and then dried, and directly dried by rotary evaporation and mixed with samples. Column chromatography gave 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. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. TLC showed that the raw materials disappeared. The reaction solution was cooled to room temperature, and insoluble impurities were removed by suction filtration. The filtrate was diluted with water and extracted with EA. The organic phase was washed once with saturated NaCl solution and then dried, and directly dried by rotary evaporation and mixed with samples. Column chromatography gave 6.5 g of compound 3. LC-MS [M+1]: 364.

[0390] 3. Synthesis of compound 4

[0391] In a 100 mL reaction kettle, 6.5 g of compound 3 and 1.3 g of palladium carbon were dissolved in 70 mL of methanol. After protecting with H2 gas, the reaction was carried out at room temperature overnight. TLC showed that the raw materials disappeared. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly dried by rotary evaporation and mixed with samples. Column chromatography gave 5.6 g of compound 4. 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. After protecting with N2 gas, the temperature was raised to 90 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction was quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and column chromatography gave 136 mg of intermediate M2. 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 intermediate compound M3 in Example 1-1 were dissolved in 1 mL of N,N-dimethylformamide. The temperature was lowered to 0 °C in an ice-water bath, and N,N-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature and reacted overnight. The reaction was detected to be complete by TLC, extracted with dichloromethane and water, the organic phase was dried, and 18 mg of compound TA-005 was obtained by column chromatography. LC-MS [M+1]: 936.

[0397] 1 H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 10.59 (s, 1H), 8.42 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.69 (d, J = 5.3 Hz, 1H), 7.53–7.41 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.81 (s, 1H), 3.98 (s, 3H), 3.91 (t, J = 6.7 Hz, 2H), 3.75 (s, 4H), 3.25 (s, 2H), 3.06 (d, J = 9.3 Hz, 2H), 2.90 (s, 2H), 2.83 (s, 2H), 2.76 (t, J = 6.7 Hz, 3H), 2.59 (dt, J = 17.8, 8.8 Hz, 3H), 2.43–2.30 (m, 2H), 2.03–1.93 (m, 1H), 1.88 (s, 1H), 1.76 (d, J = 13.5 Hz, 6H), 1.35–1.28 (m, 1H), 1.20–1.14 (m, 1H), 1.09 (t, J = 7.5 Hz, 3H).

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

[0399]

[0400]

[0401] The following chiral compounds were obtained by high-pressure preparative chromatography separation

[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] Dissolve 500 mg of Compound 1, 917 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787 mg of sodium carbonate, and 181 mg of pd(dppf)Cl2 in 10 mL of 1,4-dioxane and 1 mL of H2O in a 50 mL three-necked flask. After protecting with N2 gas, heat the mixture to 80 °C and react overnight. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction filtration, add water to the filtrate and extract with dichloromethane. Wash the organic phase once with saturated NaCl solution and then dry it. Evaporate the solvent to dryness and mix the sample. Purify by column chromatography to obtain 300 mg of Compound 2. LC-MS [M+1]: 305

[0409] 2. Synthesis of Compound 3

[0410] Add 300 mg of Compound 2 and 15 mg of palladium-carbon catalyst to a 50 mg single-necked flask, mix well with 4 mL of methanol, replace the air with a hydrogen balloon three times and then maintain it. React at room temperature overnight. After TLC detects that the reaction is complete, filter off the palladium-carbon through a diatomaceous earth pad. Evaporate the mother liquor to dryness to obtain 100 mg of Compound 3

[0411] 3. Synthesis of Intermediate M1

[0412] Dissolve 103 mg of Compound SM1, 100 mg of Compound 3, and 81 mg of p-toluenesulfonic acid monohydrate in 2 mL of isopropanol in a 100 mL reaction flask. After protecting with N2 gas, heat the mixture to 90 °C and react overnight. Monitor the reaction by TLC until it is complete. Quench with a small amount of saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate the solvent to dryness, and purify by column chromatography to obtain 50 mg of Intermediate M1. LC-MS [M+1]: 486

[0413] Synthesis of Compound TC-159

[0414]

[0415] Refer to the synthesis method of TA-003 in Example 1-1, and use Intermediate M3 in Example 1-1 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] Add 735 mg of SM1, 317 mg of dimethylphosphine oxide, 12 mL of DMF, and 3 mL of water to a 100 mL single-necked flask. After mixing evenly, displace the air with nitrogen. Then add 862 mg of potassium phosphate, 60 mg of palladium acetate, and 151 mg of Xantphos under nitrogen protection. React at 120 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 283 mg of compound 2.

[0420] 2. Synthesis of intermediate compound M1

[0421] Dissolve 140 mg of compound 2 in 3 mL of isopropanol in a 100 mL single-necked flask. Sequentially add 0.14 mL of 2,4,5-trichloropyrimidine and 0.6 mL of DIPEA. After protecting with N2 gas, heat to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Directly evaporate the reaction solution to dryness and mix the sample. Perform column chromatography to obtain 81 mg of intermediate M1. LC-MS [M+1]: 368.

[0422]

[0423] Synthesis of intermediate compound M2

[0424] Dissolve 81 mg of compound M1, 74 mg of intermediate SM2, and 54 mg of p-toluenesulfonic acid monohydrate in 2 mL of isopropanol in a 100 mL reaction tube. After protecting with N2 gas, heat to 90 °C and react overnight. Monitor the reaction by TLC until it is complete. Quench with a small amount of saturated sodium bicarbonate aqueous solution, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and perform column chromatography to obtain 76 mg of intermediate M2. LC-MS [M+1]: 567.

[0425] Synthesis of compound TA-007

[0426]

[0427] Refer to the synthesis method of TA-003 in Example 1-1 and use intermediate M3 in Example 1-1 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] Add 3.8 g of Compound 1, 5.2 ml of isopropyl pinacol borate, and 95 ml of tetrahydrofuran to a 250-ml single-necked flask, stir to dissolve, cool in an ice-water bath for 10 minutes, and slowly add 12 ml of isopropylmagnesium chloride dropwise. After reacting at room temperature for 2 hours, quench with water, extract with ethyl acetate, and purify by column chromatography to obtain 3.4 g of Compound 2.

[0433] 2. Synthesis of Intermediate M1

[0434] Add 3.4 g of Compound 2, 2.53 g of trichloropyrimidine, 2.94 g of sodium carbonate, 85 ml of acetonitrile, and 17 ml of water to a 250-ml three-necked flask. After stirring evenly, add 1 g of tetrakis(triphenylphosphine)palladium under nitrogen protection and react at 80 °C overnight. After purification by column chromatography, 1.7 g of Intermediate M1 is obtained.

[0435] Synthesis of Intermediate Compound M2

[0436]

[0437] Synthesize M2 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] Synthesize Compound TA-015 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] Add 1 g of Compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane to a 100-ml single-necked flask, mix well and displace with nitrogen, then add 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos under nitrogen protection, and react at 80 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 705 mg of Compound 2.

[0446] 2. Synthesis of Compound 3

[0447] Add 500 mg of Compound 2, 520 mg of cyclopropylboronic acid, and 5 ml of dioxane to a 100-ml single-necked flask. After mixing evenly with 1 ml of water, displace the air with nitrogen. Then add 1.7 g of potassium phosphate, 45 mg of palladium acetate, and 113 mg of tricyclohexylphosphine. Protect with nitrogen and react at 80 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 151 mg of Compound 3.

[0448] 3. Synthesis of Intermediate M1

[0449] Add 100 mg of Compound 3, 176 mg of trichloropyrimidine, 199 mg of potassium carbonate, and 2 ml of DMF to a 250-ml three-necked flask. Stir evenly and protect with nitrogen. React at 100 °C overnight. After purification by column chromatography, obtain 93 mg of Intermediate M1.

[0450] Synthesis of Compound TA-039

[0451]

[0452] Refer to the synthesis method of TA-003 in Example 1-1 and use Intermediate M3 in Example 1-1 to synthesize Compound TA-039. LC-MS [M+1]: 977.

[0453] Refer to the method of Example 1-6 to synthesize the following compounds:

[0454]

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

[0456] Synthesis of Intermediate Compound M1

[0457] The synthesis route is as follows:

[0458]

[0459] Refer to the synthesis method of Intermediate M1 in Example 1-1 to synthesize Intermediate M1.

[0460] Synthesis of Intermediate Compound M2

[0461] The synthesis 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), bis(pinacolato)diboron (1.18 g, 1.2 eq), 15 ml of 1,4-dioxane, potassium acetate (911 mg, 3.0 eq), and PdCl2(dppf) (113 mg, 0.12 eq) were mixed evenly. After purging with nitrogen, the temperature was raised to 85 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. Extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, concentrated by rotary evaporation, 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 100 ml three-necked flask, 400 mg of compound 2 (1.2 eq), 484 mg of SM1 (1.0 eq), 345 mg of potassium carbonate (3.0 eq), 10 ml of 1,4-dioxane, and 2.5 ml of water were mixed evenly under nitrogen protection. 80 mg of dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (0.12 eq) was added again, and the temperature was raised to 55 °C and the reaction was carried out for 2 hours. The reaction was monitored by TLC until completion, filtered through a diatomaceous earth pad, and the mother liquor was collected. The mother liquor was concentrated by rotary evaporation to remove the solvent, 30 ml of water was added, and extraction was performed 3 times with 15 ml of ethyl acetate. The organic phases were combined, mixed with a sample, and passed through a column. Column chromatography gave 500 mg of compound 3. LC-MS [M+1]: 462.

[0467] 3. Synthesis of compound 4

[0468] In a 50 ml single-necked flask, compound 3 (500 mg, 1.0 eq) and palladium on carbon catalyst (50 mg, 5 wt%) were added and mixed evenly with 5 ml of methanol. After purging with a hydrogen balloon 3 times, the pressure was maintained and the reaction was carried out at room temperature for 20 hours. TLC showed that the raw materials had completely reacted. Filtered through a diatomaceous earth pad, and 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, dissolved in 10 ml of tetrahydrofuran, cooled in an ice-water bath, and a 4 M hydrochloric acid dioxane solution was added dropwise. After the addition was complete, the reaction was carried out at 40 °C for 2 hours. 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] Add 330 mg of Compound 5, 4 ml of N,N-dimethylformamide, 1.2 ml of N,N-diisopropylethylamine (5.0 eq), and tert-butyl bromoacetate (195 mg, 1.1 eq) to a 100 ml single-necked flask and stir overnight at room temperature. Detect the completion of the reaction by TLC, extract with ethyl acetate and water, dry the organic phase, filter, and obtain 370 mg of Compound 6 by column chromatography. LC-MS [M+1]: 479.

[0473] 6. Synthesis of Intermediate M2

[0474] Add 350 mg of Compound 6 and 3 ml of dichloromethane to a 100 ml single-necked flask, dropwise add 2 ml of trifluoroacetic acid, stir overnight at room temperature, detect the completion of the reaction by TLC, remove the solvent by rotary evaporation to obtain 150 mg of M2. LC-MS [M-1]: 420.

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

[0476] The synthesis route is as follows:

[0477]

[0478] Dissolve Compound M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) in 4 ml of N,N-dimethylformamide in a 50 ml round-bottomed flask, cool to 0 °C in an ice-water bath, add N,N-diisopropylethylamine and HATU (176 mg, 1.3 eq) under stirring, react in an ice-water bath for 1 hour under nitrogen protection, naturally warm to room temperature, detect the completion of the reaction by TLC, extract with ethyl acetate and water, dry the organic phase, filter, and obtain 90 mg of Control Compound C1 by column chromatography. LC-MS [M+1]: 899.6.

[0479] 1H NMR (400 MHz, DMSO-d6) δ 11.69 (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 = 7.8 Hz, 1H), 7.71–7.52 (m, 3H), 7.38 (s, 1H), 7.13 (q, J = 8.5, 7.6 Hz, 2H), 6.88 (s, 1H), 4.12–3.93 (m, 6H), 3.79 (d, J = 18.4 Hz, 5H), 3.68 (s, 3H), 3.53–3.51 (m, 1H), 3.20 (d, J = 7.6 Hz, 2H), 3.10 (s, 1H), 2.98 (s, 2H), 2.93–2.78 (m, 8H), 2.69 (d, J = 7.4 Hz, 1H), 2.33 (d, J = 12.9 Hz, 1H), 2.05 (s, 1H), 1.94 (d, J = 13.0 Hz, 1H), 1.16 (t, J = 7.6 Hz, 3H).

[0480] Intermediate Preparation Example:

[0481] Synthesis of Intermediate INT-1

[0482]

[0483] Dissolve 500 mg of (2-aminophenyl)dimethylphosphine oxide in 10 mL of isopropanol in a 100 mL single-necked flask. Sequentially add 0.7 mL of 2,4,5-trichloropyrimidine and 2.9 mL of DIPEA. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Directly evaporate the reaction solution to dryness, mix the sample, and perform column chromatography to obtain 1 g of Intermediate INT-1. LC-MS [M+1]: 317.

[0484] Synthesis of Intermediate Compound INT-2

[0485]

[0486] 1. Synthesis of Compound 2

[0487] Dissolve 8.4 g of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate in 42 mL of 1,4-dioxane and 8.4 mL of H2O in a 250 mL three-necked flask. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction filtration. Add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl and then dry it. Directly evaporate the solution to dryness, mix the sample, and perform 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. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. TLC showed that the raw materials disappeared. The reaction solution was cooled to room temperature, and the insoluble impurities were removed by suction filtration. The filtrate was added with water and extracted with EA. The organic phase was washed once with saturated NaCl and then dried, and directly dried by rotary evaporation and mixed with samples. Column chromatography gave 6.5 g of Compound 3. LC-MS [M+1]: 364.

[0490] 3. Synthesis of Intermediate INT-2

[0491] In a 100 mL reaction kettle, 6.5 g of Compound 3 and 1.3 g of palladium carbon were dissolved in 70 mL of methanol. After protecting with H2 gas, the reaction was carried out at room temperature overnight. TLC showed that the raw materials disappeared. The reaction solution was filtered by suction to remove the insoluble impurities, and the filtrate was directly dried by rotary evaporation and mixed with samples. Column chromatography gave 5.6 g of Intermediate INT-2. LC-MS [M+1]: 336.

[0492] Synthesis of Intermediate INT-3

[0493]

[0494] 1. Synthesis of Compound 2

[0495] In a 50 mL three-necked flask, 500 mg of Compound 1, 917 mg of N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, 787 mg of sodium carbonate, and 181 mg of pd(dppf)Cl2 were dissolved in 10 mL of 1,4-dioxane and 1 mL of H2O. After protecting with N2 gas, the temperature was raised to 80 °C and the reaction was carried out overnight. TLC showed that the raw materials disappeared. The reaction solution was cooled to room temperature, and the insoluble impurities were removed by suction filtration. The filtrate was added with water and extracted with dichloromethane. The organic phase was washed once with saturated NaCl and then dried, and dried by rotary evaporation and mixed with samples. Column chromatography gave 300 mg of Compound 2. LC-MS [M+1]: 305

[0496] 2. Synthesis of Intermediate IN-3

[0497] In a 50 mg single-necked flask, 300 mg of Compound 2 and 15 mg of palladium carbon catalyst were added and mixed with 4 mL of methanol. After replacing the air with a hydrogen balloon three times and then maintaining it, the reaction was carried out at room temperature overnight. After TLC detected that the reaction was complete, the palladium carbon was removed by filtering with a diatomite pad, and the mother liquor was dried by rotary evaporation to obtain 100 mg of Intermediate INT-3

[0498] Synthesis of Intermediate Compound INT-4

[0499]

[0500] 1. Synthesis of Compound 2

[0501] Add 735 mg of SM1, 317 mg of dimethylphosphine oxide, 12 ml of DMF, and 3 ml of water to a 100 ml single-necked flask. After mixing evenly, displace the air with nitrogen. Then add 862 mg of potassium phosphate, 60 mg of palladium acetate, and 151 mg of Xantphos under nitrogen protection. React at 120 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 283 mg of Compound 2.

[0502] 2. Synthesis of Intermediate Compound INT-4

[0503] Dissolve 140 mg of Compound 2 in 3 ml of isopropanol in a 100 mL single-necked flask. Add 0.14 ml of 2,4,5-trichloropyrimidine and 0.6 ml of DIPEA in sequence. After protecting with N2 gas, heat to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Directly evaporate the reaction solution to dryness and mix the sample. Perform column chromatography to obtain 81 mg of Intermediate INT-4. LC-MS [M+1]: 368.

[0504] Synthesis of Intermediate Compound INT-5

[0505]

[0506] 1. Synthesis of Compound 2

[0507] Add 1 g of Compound 1, 393 mg of dimethylphosphine oxide, and 20 ml of dioxane to a 100 ml single-necked flask. After mixing evenly, displace the air with nitrogen. Then add 1066 mg of potassium phosphate, 38 mg of palladium acetate, and 97 mg of Xantphos under nitrogen protection. React at 80 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 705 mg of Compound 2.

[0508] 2. Synthesis of Compound 3

[0509] Add 500 mg of Compound 2, 520 mg of cyclopropylboronic acid, 5 ml of dioxane, and 1 ml of water to a 100 ml single-necked flask. After mixing evenly and displacing the air with nitrogen, add 1.7 g of potassium phosphate, 45 mg of palladium acetate, and 113 mg of tricyclohexylphosphine under nitrogen protection. React at 80 °C overnight. TLC shows that the reaction is complete. After extraction with ethyl acetate, purify by column chromatography to obtain 151 mg of Compound 3.

[0510] 3. Synthesis of Intermediate INT-5

[0511] Add 100 mg of Compound 3, 176 mg of trichloropyrimidine, 199 mg of potassium carbonate, and 2 ml of DMF to a 250-ml three-necked flask. After stirring evenly, protect with nitrogen and react at 100 °C overnight. After purification by column chromatography, 93 mg of Intermediate INT-5 was obtained.

[0512] Synthesis of Intermediate Compound INT-6

[0513]

[0514] Dissolve 8.3 g of SM1 in 100 mL of dichloromethane in a 250-mL three-necked flask. After protecting with N2 gas, add triethylamine. Cool to 0 °C in an ice bath and slowly add TF2O dropwise. React at room temperature overnight. Monitor the reaction by TLC until it is complete. Add water to the reaction solution and extract with EA. Wash the organic phase once with saturated NaCl, dry it, evaporate to dryness, mix the sample, and perform column chromatography to obtain 2 g of Intermediate INT-6.

[0515] Synthesis of Intermediate Compound INT-7

[0516]

[0517] Synthesis of Compound 2

[0518] Add 6.7 g of SM1, 15.2 ml of 1,2-dibromoethane, and 14.5 g of potassium carbonate dissolved in 67 ml of ACN to a 250-ml single-necked flask. Heat at 85 °C and react overnight. After TLC shows that the reaction is complete, wait for the reaction solution to cool to room temperature, evaporate to dryness, and perform column chromatography to obtain 8.47 g of Compound 2.

[0519] Synthesis of Compound 3

[0520] Add 3 g of Compound 2 to a 250-ml three-necked flask. After dissolving it with 38 ml of THF, protect with nitrogen. Cool to -78 °C in an environment of -80 °C, slowly add 4 ml of n-butyllithium dropwise. After the addition is complete, continue to react at -78 °C for 2 h and stir at room temperature overnight. After TLC detects that the reaction is complete, quench with ammonium chloride under ice bath conditions, evaporate the organic solvent, extract with ethyl acetate, dry the organic phase, evaporate to dryness, and perform column chromatography to obtain 1.2 g of colorless oily Compound 3.

[0521] Synthesis of Compound 4

[0522] Add 1.2 g of Compound 3 to a 100-ml single-necked flask. After dissolving it with 12 ml of ACN, protect with nitrogen. Stir in an ice bath for 10 min, add 1.7 g of NBS, and stir at room temperature for 2 h. After the reaction is complete, purify by column chromatography to obtain 1.6 g of Compound 4.

[0523] Synthesis of Compound 5

[0524] Dissolve 1.6 g of Compound 4 in 13 ml of TFA in a 100-ml single-necked flask, protect with nitrogen, stir for 10 min in an ice bath, add sodium nitrite, and allow to warm to room temperature and react overnight. After detecting the completion of the reaction by TLC, concentrate to remove TFA, quench the remaining solution with saturated sodium bicarbonate, extract with ethyl acetate, dry and concentrate the organic phase, and purify by column chromatography to obtain 874 mg of Compound 5.

[0525] Synthesis of Compound 6

[0526] Add 874 mg of Compound 5, 212 mg of N-Boc piperazine, and 210 mg of potassium carbonate to a 10-ml reaction tube, dissolve in 4 ml of DMF, protect with nitrogen, and heat at 65 °C overnight. After detecting the completion of the reaction by TLC, cool the reaction solution to room temperature, add water and extract with ethyl acetate. Wash the organic phase twice with saturated brine, dry and concentrate, and purify by column chromatography to obtain 189 mg of Compound 6.

[0527] Synthesis of Compound 7

[0528] Add 189 mg of Compound 6, 118 mg of C2H3BF3K, 91 mg of potassium carbonate, and 32 mg of Pd(dppf)Cl2 to a 10-ml reaction tube, dissolve in 2 ml of 1,4-dioxane, add 0.4 ml of water, protect with nitrogen, and heat at 100 °C for 4 h. After detecting the completion of the reaction by TLC, cool the reaction solution to room temperature and purify by column chromatography to obtain 135 mg of Compound 7.

[0529] Synthesis of Intermediate INT-7

[0530] Add 135 mg of Compound 7 and 13 mg of palladium-carbon to a 10-ml reaction tube, dissolve in 3 ml of methanol, protect with hydrogen, and react at room temperature overnight. After detecting the completion of the reaction by TLC, filter off the palladium-carbon by suction, and concentrate the filtrate to obtain 137 mg of INT-7.

[0531] Synthesis of Intermediate Compound INT-8

[0532]

[0533] Synthesis of Compound 2

[0534] Add 1 g of SM1, 0.83 g of tert-butyl bromoacetate, 2.2 g of cesium carbonate, and 10 ml of acetonitrile to a 100-ml single-necked flask. Heat to 55 °C under nitrogen protection and react for 7 hours. After TLC shows the completion of the reaction, remove the solvent by rotary evaporation, mix the sample and pass through a column to obtain 1.4 g of a pale yellow oily product, Compound 2.

[0535] Synthesis of Compound 3

[0536] Add 200 mg of SM2, 257 mg of Compound 2, 381 mg of cesium carbonate, 64 mg of Pd(dppf)Cl2, 10 ml of 1,4-dioxane, and 1 ml of water to a 100 ml single-necked flask. Heat the reaction mixture to 90 °C under nitrogen protection and stir overnight. After the reaction is completed as indicated by TLC, directly perform column chromatography to obtain 100 mg of 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 flask. Slowly add 1 ml of trifluoroacetic acid dropwise and react at room temperature for 3 hours. Rotavapor the reaction mixture to obtain the crude product for the next step.

[0539] Synthesis of Intermediate Compound INT-9

[0540]

[0541] Synthesis of Compound 2

[0542] In a 250 ml single-necked flask, heat 5 g of Compound 1 and 5 ml of ammonia water in 10 ml of n-butanol to 120 °C and stir overnight. After the reaction is completed as indicated by TLC, add water and ethyl acetate to extract the reaction mixture. Combine the organic phases, rotavapor, and perform column chromatography. Obtain 3.8 g of Compound 2

[0543] Synthesis of Compound 3

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

[0545] Synthesis of Compound 4

[0546] Add 1 g of Compound 3, 510 mg of phenylboronic acid, 750 mg of copper acetate, 0.5 ml of pyridine, and 50 ml of dichloromethane to a 100 ml single-necked flask. Mix well, displace with an oxygen balloon three times. React overnight under an oxygen atmosphere. After the reaction is complete as indicated by TLC, filter by suction to collect the mother liquor, rotavapor, and purify by column chromatography to obtain 200 mg 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-necked flask, and stir at room temperature overnight. After TLC shows the reaction is complete, remove methanol by rotary evaporation, then extract the reaction solution with ethyl acetate. Combine the organic phases and purify by column chromatography 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 evenly 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 the reaction is complete, cool to room temperature, and adjust the pH to 7-8 with 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, filter by suction, and collect the filter cake, 150 mg. 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 evenly. Heat to 60 °C and react overnight. Add 1.5 ml of 2N hydrochloric acid and maintain for 3 hours. Turn off the heating, cool to room temperature, precipitate solid, filter by suction, and collect the filter cake to obtain 80 mg of Compound 7.

[0553] Synthesis of Compound 8

[0554] Disperse 500 mg of Compound 7, 632 mg of bis(pinacolato)diboron, 1.2 g of potassium acetate, and 45 mg of Pd(dppf)Cl2 evenly in 1,4-dioxane. After purging with nitrogen three times, heat to 80 °C under nitrogen protection and react overnight. After TLC shows the raw materials have completely reacted, directly mix with sample and separate by column chromatography to obtain 560 mg of Compound 8. LC-MS: 451.

[0555] Synthesis of Compound 9

[0556] Disperse 560 mg of Compound 8, 538 mg of M3 from Example 2, 404 mg of sodium carbonate, and 100 mg of Pd(dppf)Cl2 evenly in 6 ml of 1,4-dioxane and 0.6 ml of water. After purging with nitrogen, heat to 55 °C under nitrogen protection and react for 2 hours.

[0557] When TLC shows no raw materials, end the reaction. Spin-dry the reaction solution and then purify by column chromatography 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. React at room temperature for 4 hours. LC-MS shows that there is no raw material remaining. Rotavap the reaction solution for the next step.

[0560] Synthesis of Compound 11

[0561] Dissolve 380 mg of Compound 10, 53 mg of tert-butyl bromoacetate, and 0.2 ml of DIPEA in 2 ml of DMF. React at room temperature overnight. After TLC shows the reaction is complete, extract the reaction solution with ethyl acetate. Combine the organic phases and column chromatograph to obtain 350 mg of Compound 11. LC-MS: 556

[0562] Synthesis of Compound 12

[0563] Add 300 mg of Compound 11 and 60 mg of palladium on carbon catalyst to a mixture of 3 ml of methanol and 3 ml of ethyl acetate. Mix well and displace with hydrogen 3 times. Seal with a hydrogen balloon and react at 35 °C overnight. After TLC shows the reaction is complete, filter through a diatomaceous earth pad, collect the mother liquor, and rotavap and column chromatograph to obtain 170 mg of Compound 12. LCMS: 558

[0564] Synthesis of Compound INT-9

[0565] Dissolve 170 mg of Compound 12 in 2 ml of dichloromethane, add 1.7 ml of trifluoroacetic acid dropwise, and react at room temperature for 3 hours. After completion, rotavap to obtain 150 mg of Compound INT-9

[0566] Synthesis of Intermediate INT-10

[0567] The synthesis route is as follows:

[0568]

[0569] 1. Synthesis of Compound 2

[0570] In a 100 ml single-neck flask, mix 1.0 g (1.0 eq) of Compound 1, bis(pinacolato)diboron (1.18 g, 1.2 eq), 15 ml of 1,4-dioxane, potassium acetate (911 mg, 3.0 eq), and PdCl2dppf (113 mg, 0.12 eq) evenly. After displacing with nitrogen, heat to 85 °C and react overnight. Monitor the reaction by TLC until complete. Extract with ethyl acetate, dry over anhydrous sodium sulfate, rotavap, and separate 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 100 ml three-necked flask, 400 mg of Compound 2 (1.2 eq), 484 mg of SM1 (1.0 eq), 345 mg of potassium carbonate (3.0 eq), 10 ml of 1,4-dioxane, and 2.5 ml of water were mixed evenly under nitrogen protection. Then, 80 mg of dichloropalladium (II) bis(diphenylphosphino)ferrocene (0.12 eq) was added, and the temperature was raised to 55 °C for 2 hours of reaction. The reaction was monitored by TLC until completion, filtered through a diatomaceous earth pad, and the mother liquor was collected. The solvent was removed by rotary evaporation, 30 ml of water was added, and the mixture was extracted three times with 15 ml of ethyl acetate. The organic phases were combined, mixed with a sample, and purified by column chromatography to obtain 500 mg of Compound 3. LC-MS [M+1]: 462..

[0573] 3. Synthesis of Compound 4

[0574] In a 50 ml single-necked flask, Compound 3 (500 mg, 1.0 eq), palladium on carbon catalyst (50 mg, 5 wt%), and 5 ml of methanol were mixed evenly. After replacing the air with a hydrogen balloon three times, the pressure was maintained, and the reaction was carried out at room temperature for 20 hours. TLC showed that the raw material reaction was complete. Filtered through a diatomaceous earth pad, and the mother liquor was collected to obtain 400 mg of Compound 4.

[0575] 4. Synthesis of Compound 5

[0576] In a 100 ml single-necked flask, 400 mg of Compound 4 was added, dissolved in 10 ml of tetrahydrofuran, and cooled in an ice-water bath. A 4 M hydrochloric acid dioxane solution was added dropwise, and after the addition was complete, the reaction was carried out at 40 °C for 2 hours. 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] In a 100 ml single-necked flask, 330 mg of Compound 5, 4 ml of N,N-dimethylformamide, 1.2 ml of N,N-diisopropylethylamine (5.0 eq), and tert-butyl bromoacetate (195 mg, 1.1 eq) were added and stirred overnight at room temperature. The reaction was monitored by TLC until completion, extracted with ethyl acetate and water, the organic phase was dried, filtered, and purified by 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 flask, 350 mg of Compound 6 and 3 ml of dichloromethane were added, and 2 ml of trifluoroacetic acid was added dropwise. The mixture was stirred overnight at room temperature. The reaction was monitored by TLC until completion, and 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] Dissolve 8.4 g of SM1, 9 g of boron trifluoride, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate in 42 mL of 1,4-dioxane and 8.4 mL of H2O in a 250 mL three-necked flask. After protecting with N2 gas, heat the mixture to 100 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction, add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl solution, dry it, and directly evaporate to dryness and mix with the sample. Perform column chromatography to obtain 5.3 g of Compound 2. LC-MS [M+1]: 198.

[0586] 2. Synthesis of Compound 3

[0587] 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 to a 50 ml single-necked flask. Dissolve them in 10 ml of dimethylacetamide and protect with nitrogen gas. Heat the reaction mixture at 110 °C for 5 h. After detecting the completion of the reaction by TLC, cool the reaction solution to room temperature, add water and extract with ethyl acetate. Wash the organic phase twice with saturated brine, dry and concentrate it, and perform column chromatography to obtain 6 g of yellow solid Compound 3. LC-MS [M+1]: 404.

[0588] 3. Synthesis of Intermediate INT-11

[0589] Add 6 g of Compound 3 and 60 mg of palladium carbon to a 100 ml single-necked flask. Dissolve them in 60 ml of absolute ethanol and protect with hydrogen gas. React at room temperature. After the reaction is completed, filter off the palladium carbon by suction, and concentrate the filtrate to obtain 1.9 g of Intermediate INT-11. LC-MS [M+1]: 376.

[0590] Synthesis of Intermediate Compound INT-12

[0591]

[0592] Synthesis of Compound 2

[0593] Mix 1.15 g of tert-butyl acetate and 20 ml of dry tetrahydrofuran evenly and protect with nitrogen gas. Cool the mixture to -78 °C, slowly add 11.8 ml of LDA dropwise, keep the temperature for half an hour, then add dropwise a 20 ml tetrahydrofuran dilution of 3 g of SM1, and keep the temperature low for 1 h. After the reaction is completed, quench the reaction solution with saturated ammonium chloride aqueous solution, and extract with ethyl acetate. Dry and filter the organic phase to obtain 4.38 g of Compound 2.

[0594] Synthesis of Compound 3

[0595] 4.38 g of Compound 2 and 1.31 g of palladium hydroxide on carbon were mixed in a 100 ml autoclave, then 1,4-dioxane was added and dispersed evenly. After replacing hydrogen three times, the reaction was carried out at room temperature overnight. After the reaction, the mother liquor was collected by filtration through a diatomaceous earth pad and rotary evaporated for standby.

[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. Under nitrogen protection, the mixture was heated to 100 °C and reacted overnight. After monitoring the reaction by TLC until completion, the sample was directly mixed and rotary evaporated, and then purified by column chromatography 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 1,4-dioxane solution of hydrogen chloride was added dropwise. The reaction was carried out at room temperature for 3 hours. After confirming the completion of the reaction by LCMS, the solvent was removed by rotary evaporation to obtain the crude product of Compound INT-12.

[0600] Synthesis of Intermediate Compound INT-13

[0601]

[0602] Synthesis of Compound 2

[0603] 500 mg of SM1, 558 mg of boc-piperazine, and 552 mg of potassium carbonate were added to a 100 ml single-necked flask and dissolved in 10 ml of DMAC. The mixture was heated at 90 °C overnight. After the reaction was shown to be complete by TLC, the reaction solution was extracted with ethyl acetate and water. The ethyl acetate phase was dried, filtered, and rotary evaporated, and then purified by column chromatography to obtain 760 mg of Compound 2.

[0604] Synthesis of Compound 3

[0605] 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 to a 100 ml single-necked flask and mixed. After replacing with a carbon monoxide balloon three times and sealing with a balloon, the reaction was carried out at 85 °C overnight. After detecting the completion of the reaction by TLC, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, rotary evaporated, and purified by column chromatography to obtain 150 mg of yellow oily Compound 3. LC-MS [M+1]: 418

[0606] Synthesis of Intermediate INT-13

[0607] In a 100 ml single-necked flask, add 150 mg of compound 3, 10 mg of palladium on carbon, and 3 ml of methanol. After mixing, react at 35 °C overnight. After the reaction is completed, filter through a diatomaceous earth pad, collect the mother liquor, and concentrate it to dryness to obtain the crude compound INT-13.

[0608] Synthesis of Intermediate Compound INT-14

[0609] The synthesis route is as follows:

[0610]

[0611] 1. Synthesis of Compound 2

[0612] Add 10 g of magnesium shavings and two iodine grains to a 500 ml three-necked flask. After protecting with N2, add 150 ml of tetrahydrofuran to dissolve. Add 0.1 ml of 1,4-dibromobutane to initiate the reaction. Cool the reaction solution to 0 °C. Dissolve 12 ml of 1,4-dibromobutane in 40 ml of tetrahydrofuran and slowly add it dropwise, controlling the temperature below 30 °C. After the addition is complete, react at room temperature for 2 - 3 hours; cool the solution to 0 °C, slowly add 6.8 ml of diethyl phosphite dropwise, controlling the temperature below 20 °C. After the addition is complete, react at room temperature. After the reaction is completed as indicated by TLC, cool the reaction solution to 0 °C, slowly add a potassium carbonate solution (30 g of K2CO3 and 50 g of H2O) to quench the reaction, controlling the temperature below 10 °C. A large amount of solid precipitates. Filter by suction, concentrate the filtrate to dryness, and purify by column chromatography to obtain 1.1 g of a colorless transparent liquid compound 2. LC-MS [M + 1]: 105.

[0613] 2. Synthesis of Compound 3

[0614] Add 1.1 g of compound 2, 1.1 g of iodoaniline, 1.6 g of potassium phosphate, 152 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and 59 mg of palladium acetate to a 100 ml single-necked flask. After dissolving with 24 ml of 1,4-dioxane and protecting with nitrogen, heat the reaction at 80 °C overnight. After the reaction is completely detected by TLC, cool the reaction solution to room temperature, filter by suction, concentrate the filtrate to dryness, and purify by column chromatography to obtain 611 mg of a brown oily compound 3. LC-MS [M + 1]: 196.

[0615] 3. Synthesis of Intermediate INT-14

[0616] Add 300 mg of compound 3, 649 mg of 2,4-dichloro-5-bromopyrimidine, and 1.5 ml of N,N-diisopropylethylamine to a 100 ml single-necked flask. After dissolving with 6 ml of isopropanol and protecting with nitrogen, heat the reaction at 100 °C. After the reaction is completed, purify by column chromatography to obtain 309 mg of intermediate INT-14. 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] Dissolve 2 g of SM1, 2.2 g of bis(pinacolato)diboron, 2.4 g of pd(dppf)Cl2, and 1.7 g of potassium acetate in 30 mL of 1,4-dioxane in a 100 mL three-necked flask. After protecting with N2 gas, heat the mixture to 85 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction, add water to the filtrate and extract with EA. Wash the organic phase once with saturated NaCl, dry it, directly evaporate to dryness and mix with the sample, and perform column chromatography to obtain 2 g of Compound 2. LC-MS [M+1]: 389.

[0622] 2. Synthesis of Compound 3

[0623] Dissolve 2 g of Compound 2, 2 g of SM2, 1.5 g of sodium carbonate, and 376 mg of pd(dppf)Cl2 in 40 mL of 1,4-dioxane and 10 mL of H2O in a 250 mL three-necked flask. After protecting with N2 gas, heat the mixture to 55 °C and react for 2 h. Monitor the reaction by TLC until the raw materials disappear. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction, add water to the filtrate and extract with dichloromethane. Wash the organic phase once with saturated NaCl, dry it, evaporate to dryness and mix with the sample, and perform column chromatography to obtain 1.8 g of Compound 3. LC-MS [M+1]: 480.

[0624] 3. Synthesis of Compound 4

[0625] Dissolve 1.8 g of Compound 3 in 18 mL of ethyl acetate in a 100 mL single-necked flask, add 1,4-dioxane hydrochloride, and react overnight at room temperature. Monitor the reaction by TLC until the raw materials disappear. Filter the reaction solution by suction to obtain 1 g of filter cake, which is Compound 4. LC-MS [M+1]: 380.

[0626] 4. Synthesis of Compound 5

[0627] Dissolve 1 g of Compound 4 in 10 mL of DMF in a 100 mL three-necked flask. After protecting with N2 gas, add 2 mL of N,N-diisopropylethylamine, stir for 10 min in an ice bath, then add 0.4 mL of tert-butyl bromoacetate, and react overnight at room temperature. Monitor the reaction by TLC until it is complete. Add water to the reaction solution and extract with ethyl acetate. Dry it with anhydrous sodium sulfate, evaporate to dryness, and perform column chromatography to obtain 1.5 g of Compound 5. LC-MS [M+1]: 494.

[0628] 5. Synthesis of Compound 6

[0629] Dissolve 1.5 g of Compound 5 and 228 mg of palladium carbon in 30 mL of methanol in a 100 mL reaction kettle. After protecting with H2 gas, react overnight at room temperature. TLC shows that the raw materials disappear. Filter the reaction solution by suction to remove insoluble impurities. Directly evaporate the filtrate to dryness and mix the sample. Obtain 200 mg of Compound 6 by column chromatography. LC-MS [M+1]: 496.

[0630] 6. Synthesis of Intermediate INT-15

[0631] Add 200 g of Compound 6 to a 100 mL reaction tube, dissolve it in 1 mL of dichloromethane, add 0.2 mL of trifluoroacetic acid, and react overnight at room temperature. TLC shows that the raw materials disappear. Concentrate the reaction solution 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 synthesis route is as follows:

[0634]

[0635] 1. Synthesis of Compound 2

[0636] Dissolve 1 g of SM1 in 20 mL of DMF in a 100 mL three-necked flask. After protecting with nitrogen, add 260 mg of sodium hydride under ice bath, then add 810 mg of 2-iodopropane, and react at room temperature for 1 h. Monitor the reaction by TLC until it is complete. Quench the reaction solution with saturated ammonium chloride, add water and extract with EA. Wash the organic phase once with saturated NaCl and then dry it. Directly evaporate the solvent to dryness and mix the sample. Obtain 776 mg of Compound 2 by column chromatography. LC-MS [M+1]: 274.

[0637] 2. Synthesis of Compound 3

[0638] Dissolve 776 mg of Compound 2, 0.3 mL of acrylic acid, and 92 mg of tetrabutylammonium bromide in 8 mL of 2 M hydrochloric acid solution in a 250 mL three-necked flask. After protecting with N2 gas, heat to 100 °C and react overnight. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, quench it with saturated sodium carbonate under ice bath until the pH is 9, then adjust the pH to 3 - 4 with acetic acid. A large amount of white solid precipitates. Stir well and then filter. Dry the filter cake to obtain 1.2 g of Compound 3. LC-MS [M+1]: 346.

[0639] 3. Synthesis of Compound 4

[0640] Dissolve 1.2 g of Compound 3 in 12 mL of acetic acid in a 100 mL single-necked flask, add 453 mg of sodium cyanate, and heat the reaction at 60 °C for 14 h. Add it to 12 mL of 2 M hydrochloric acid solution, and continue the reaction at 60 °C for 3 h. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, quench it with saturated sodium carbonate solution, add water and extract with ethyl acetate. Dry and concentrate the organic phase, and obtain 330 mg of Compound 4 by column chromatography. LC-MS [M+1]: 369.1.

[0641] 4. Synthesis of Compound 5

[0642] Dissolve 330 mg of Compound 4, 340 mg of bis(pinacolato)diboron, 65 mg of pd(dppf)Cl2, and 262 mg of potassium acetate in 7 mL of 1,4-dioxane in a 100 mL three-necked flask. After protecting with N2 gas, heat the reaction to 85 °C and react overnight. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction, spin-dry the filtrate and mix the sample, and obtain 434 mg of Compound 5 by column chromatography. LC-MS [M+1]: 417.

[0643] 5. Synthesis of Compound 6

[0644] Dissolve 434 mg of Compound 5, 421 mg of SM2, 316 mg of sodium carbonate, and 76 mg of pd(dppf)Cl2 in 4 mL of 1,4-dioxane and 2 mL of H2O in a 50 mL single-necked flask. After protecting with N2 gas, heat the reaction to 55 °C and react for 2 h. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, filter off the insoluble impurities by suction, dry the filtrate, spin-dry and mix the sample, and obtain 265 mg of Compound 6 by column chromatography. LC-MS [M+1]: 508.

[0645] 6. Synthesis of Compound 7

[0646] Dissolve 265 mg of Compound 6 in 3 mL of ethyl acetate in a 50 mL single-necked flask, add 2 mL of 1,4-dioxane hydrochloric acid, and react overnight at room temperature. TLC shows that the raw materials disappear. Filter the reaction solution by suction to obtain 142 mg of filter cake, which is Compound 7. LC-MS [M+1]: 408.

[0647] 7. Synthesis of Compound 8

[0648] Dissolve 142 mg of Compound 7 in 3 mL of DMF in a 50 mL single-necked flask. After protecting with N2 gas, add 0.28 mL of N,N-diisopropylethylamine, stir for 10 min in an ice bath, then add 0.06 mL of tert-butyl bromoacetate, and react overnight at room temperature. Monitor the reaction by TLC until it is complete. Add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, spin-dry, and obtain 174 mg of Compound 8 by column chromatography. LC-MS [M+1]: 522.4.

[0649] Synthesis of Compound 9

[0650] Dissolve 174 mg of Compound 8 and 17 mg of palladium on carbon in 4 mL of methanol and 4 mL of ethyl acetate in a 50 mL single-necked flask. After protecting with H2 gas, react at room temperature overnight. TLC shows that the raw materials disappear. Filter the reaction solution by suction to remove insoluble impurities. Directly evaporate the filtrate to dryness and mix the sample. Column chromatography gives 142 mg of Compound 9. LC-MS [M+1]: 524.

[0651] Synthesis of Intermediate INT-16

[0652] Add 142 mg of Compound 9 to a 10 mL reaction tube, dissolve it in 2 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature overnight. TLC shows that the raw materials disappear. Concentrate the reaction solution 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 synthesis route is as follows:

[0655]

[0656] 1. Synthesis of Compound 2

[0657] Mix 300 mg of Compound 1 (1.0 equivalent), 272 mg of SM2 (1.0 equivalent), 280 mg of sodium carbonate (1.5 equivalents), 6 mL of 1,4-dioxane, and 1.5 mL of water evenly in a 50 mL single-necked flask and protect with nitrogen. Add 63 mg of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.1 equivalent) again, displace with nitrogen three times and heat to 100 °C, and react overnight. Monitor the reaction by TLC until it is complete. Filter through a diatomaceous earth pad, collect the mother liquor, evaporate the mother liquor to remove the solvent, add 30 mL of water, and extract with 15 mL of ethyl acetate three times. Combine the organic phases, mix the sample and pass through a column. Column chromatography gives 345 mg of Compound 2.

[0658] 2. Synthesis of Compound 3

[0659] Add 345 mg of Compound 2 and 34.5 mg of Pd / C to 3.4 mL of MeOH in a 50 mL single-necked flask. Displace with hydrogen three times and react at room temperature for 6 h under the protection of a hydrogen balloon. After the reaction is completed, filter the reaction solution to remove the palladium carbon. Evaporate the filtrate 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-necked flask, 345 mg of Compound 3 and 2 mL of hydrochloric acid dioxane solution were added to 3 mL of THF, and the reaction was carried out 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 protecting with N2 gas, 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, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until complete. The reaction solution was added with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography to obtain 690 mg of Compound 5. LC-MS [M+1]: 460.

[0664] 5. Synthesis of Intermediate INT-17

[0665] In a 100 mL reaction tube, 363 mg of Compound 6 was dissolved in 1 mL of dichloromethane. After adding 0.2 mL of trifluoroacetic acid, the reaction was carried out overnight at room temperature. TLC showed that the raw material disappeared. 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 of SM1 and 1.06 g of dimethyloxyphosphine were dissolved in 20 mL of NN-dimethylformamide. After protecting with N2 gas, 2.9 g of potassium phosphate, 204 mg of palladium acetate, and 525 mg of Xnatphos were added. After purging with nitrogen three times, the reaction was carried out at 115 °C overnight. The reaction was monitored by TLC until complete. The reaction solution was added with water and extracted with EA. The organic phase was washed once with saturated NaCl and then dried, evaporated to dryness, and mixed with samples, and purified by column chromatography to obtain 350 mg of Compound 2.

[0670] Synthesis of Intermediate INT-18

[0671] In a 100 mL single-necked flask, 300 mg of Compound 2, 649 mg of trichloropyrimidine, and 1.5 mL of N,N-diisopropylethylamine were dissolved in 6 mL of isopropanol. After protecting with nitrogen, the reaction was heated at 100 °C. After the reaction was completed, it was purified by column chromatography to obtain 309 mg of Intermediate INT-18. 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] Dissolve 29 g of SM1 in 290 ml of absolute ethanol in a 500 mL three-necked flask, protect with nitrogen, add 35 ml of methylhydrazine, and heat the reaction at 80 °C. Monitor the reaction by TLC until it is complete. Cool the reaction solution to room temperature, stir well in an ice bath, and a large amount of white solid will precipitate. Filter to obtain the filter cake, and after drying the filter cake, 15.7 g of the product is obtained; the product is obtained by column chromatography of the filtrate, 9 g; a total of 24.7 g of light yellow solid Compound 2 is obtained. LC-MS [M+1]: 246.1.

[0677] 2. Synthesis of Compound 3

[0678] Dissolve 24.7 g of Compound 2, 10.4 ml of acrylic acid, and 3.2 g of tetrabutylammonium bromide in 250 mL of 2M hydrochloric acid solution in a 500 mL three-necked flask, and heat the reaction at 100 °C overnight. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, quench it with saturated sodium carbonate in an ice bath, adjust the pH to 9, and then adjust the pH to 3-4 with acetic acid. A large amount of white solid will precipitate. After stirring well, filter, and after drying the filter cake, 26 g of yellow solid Compound 3 is obtained. LC-MS [M+1]: 316.1.

[0679] 3. Synthesis of Intermediate INT-19

[0680] Dissolve 26 g of Compound 3 in 260 mL of acetic acid in a 1 L single-necked flask, add 10.6 g of sodium cyanate, and heat the reaction at 60 °C for 14 h. Add it to 260 ml of 2M hydrochloric acid solution, and continue to react at 60 °C for 3 h. TLC shows that the raw materials disappear. Cool the reaction solution to room temperature, stir well in an ice bath, and a large amount of white solid will precipitate. Filter, and after drying the filter cake, 10.7 g of yellow solid INT-19 is obtained. 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 successively added. After dissolving with 2 mL of isopropanol, under nitrogen protection, the reaction was heated at 105 °C overnight. After detecting the completion of the reaction by TLC, 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] In a 10 mL reaction tube, 73 mg of compound 2 and 1 mL of trifluoroacetic acid were added. After dissolving with 2 mL of dichloromethane, the reaction was carried out at room temperature for 0.5 h. After detecting the completion of the reaction by TLC, 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] In a 10 mL reaction tube, 116 mg of intermediate INT-15 was added. After dissolving with 2 mL of DMF, 0.15 mL of DIPEA was added. Under nitrogen protection, the mixture was stirred in an ice bath for 10 min, then 58 mg of compound 3 and 45 mg of HATU were added, and the reaction was carried out at room temperature overnight. After detecting the completion of the reaction by TLC, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried and concentrated, and purified by column chromatography to obtain 17 mg of compound TB-006. LC-MS [M+1]: 1047 HPLC: 96%

[0691] 1 H NMR (400 MHz, DMSO) δ 10.58 (s, 2H), 8.30 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 5.2 Hz, 1H), 7.45 (dd, J = 18.0, 9.1 Hz, 2H), 7.35 (s, 1H), 7.14 (s, 2H), 6.15 (s, 1H), 4.03 (s, 4H), 3.92 (t, J = 6.5 Hz, 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 = 13.0 Hz, 1H), 1.18 (t, J = 7.1 Hz, 1H), 1.02 (t, J = 7.3 Hz, 3H).

[0692] With reference to the synthesis methods of intermediate compound INT-14 and compound TB-006, the following compounds were synthesized respectively:

[0693]

[0694] The following chiral compounds were obtained by preparative high-pressure chromatography separation

[0695]

[0696]

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

[0698]

[0699] The synthesis route is as follows:

[0700]

[0701] Dissolve 50 mg of compound 3 and 75 mg of INT-17 in 3 mL of DMF in a 50 mL round-bottom flask, then add 0.14 mL of DIPEA and 40 mg of HATU. After purging with N2 three times, react at room temperature for 3 h. TLC shows that the reaction is complete. The reaction solution is extracted with ethyl acetate and water, then concentrated under reduced pressure and mixed with sample. After column chromatography, 19 mg of compound TB-008 is obtained. LC-MS [M+1]: 1012.5. 1H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 10.57 (s, 1H), 8.31 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.57 (d, J = 5.9 Hz, 1H), 7.46 (dd, J = 13.5, 7.7 Hz, 1H), 7.38 (d, J = 10.9 Hz, 2H), 7.14 (s, 2H), 6.14 (s, 1H), 4.01 (s, 3H), 3.90 (t, J = 6.6 Hz, 2H), 3.71 (d, J = 21.6 Hz, 7H), 3.22 (s, 2H), 2.99 (d, J = 10.8 Hz, 3H), 2.85 (s, 2H), 2.75 (t, J = 6.5 Hz, 2H), 2.40 (d, J = 7.5 Hz, 2H), 2.26–1.64 (m, 20H), 1.02 (t, J = 7.4 Hz, 3H).

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

[0703]

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

[0705]

[0706] The synthesis route is as follows:

[0707]

[0708] Synthesis of Compound TB-018

[0709] Add 78 mg of intermediate INT-16 into a 10 ml reaction tube. After dissolving with 1 ml of DMF, add 0.13 ml of DIPEA. Under nitrogen protection, stir for 10 min in an ice bath. Add 50 mg of Compound 3 and 39 mg of HATU, and react overnight at room temperature. After detecting the completion of the reaction by TLC, add water to the reaction solution and extract with ethyl acetate. The organic phase is washed twice with saturated brine and then dried and concentrated. After purification by column chromatography, 22 mg of Compound TB-018 is obtained. 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=22.7Hz,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 respectively:

[0712]

[0713] Example 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 of SM1, 9 g of potassium vinyltrifluoroborate, 2.4 g of pd(dppf)Cl2, and 6.9 g of potassium carbonate were dissolved in 42 mL of 1,4-dioxane and 8.4 mL of H2O. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and insoluble impurities were removed by suction filtration. The filtrate was diluted with water and extracted with EA. The organic phase was washed once with saturated NaCl solution and then dried, and directly concentrated to dryness and mixed with silica gel. Column chromatography gave 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-butoxycarbonylaminopiperidine, and 631 mg of potassium carbonate were dissolved in 10 mL of DMAC. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. TLC showed that the starting materials disappeared. The reaction solution was cooled to room temperature, and insoluble impurities were removed by suction filtration. The filtrate was diluted with water and extracted with EA. The organic phase was washed once with saturated NaCl solution and then dried, and directly concentrated to dryness and mixed with silica gel. Column chromatography gave 400 mg of compound 3. LC-MS [M+1]: 378.

[0721] 3. Synthesis of compound 4

[0722] In a 100 mL single-necked flask, 400 mg of compound 3 and 20 mg of palladium carbon were dissolved in 10 mL of methanol. After protecting with H2 gas, the reaction was carried out at room temperature overnight. TLC showed that the starting materials disappeared. The reaction solution was filtered to remove insoluble impurities, and the filtrate was directly concentrated to dryness and mixed with silica gel. Column chromatography gave 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. After protecting with N2 gas, the temperature was raised to 90 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction was quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to dryness, and column chromatography gave 70 mg of intermediate M2. 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 N,N-dimethylformamide. The temperature was lowered to 0 °C in an ice-water bath, and N,N-diisopropylethylamine and HATU were added with stirring. The reaction was carried out in an ice-water bath under nitrogen protection for 1 hour, then naturally warmed to room temperature and reacted overnight. The reaction was detected to be complete by TLC, extracted with dichloromethane and water, the organic phase was dried, and 18 mg of TC-085 was obtained by column chromatography. LC-MS [M+1]: 950.7.

[0728] 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.61 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.74 (d, J = 6.4 Hz, 2H), 7.55 (dd, J = 14.1, 7.7 Hz, 1H), 7.44 (d, J = 9.5 Hz, 2H), 7.32 (s, 1H), 7.11 (t, J = 7.2 Hz, 1H), 6.82 (s, 1H), 4.02 (s, 3H), 3.92 (t, J = 6.8 Hz, 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 = 7.6 Hz, 4H), 1.88 (s, 3H), 1.77 (d, J = 13.5 Hz, 5H), 1.65 (d, J = 11.2 Hz, 2H), 1.07 (t, J = 7.5 Hz, 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 following chiral compounds were obtained by high-pressure preparative chromatography separation

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

[0737]

[0738] Synthesis of Compound TC-113

[0739]

[0740] With reference 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) δ 10.60 (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), 3.91 (t, J = 6.7 Hz, 2H), 3.69 (d, J = 27.8 Hz, 7H), 3.56 (d, J = 11.7 Hz, 2H), 3.45 (s, 3H), 3.04 (d, J = 10.8 Hz, 1H), 2.77 (dd, J = 19.0, 12.1 Hz, 8H), 2.39 (s, 4H), 1.85 (d, J = 12.1 Hz, 1H), 1.64 (d, J = 13.6 Hz, 6H), 0.95 (s, 3H).

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

[0742]

[0743] Synthesis of Compound TC-117

[0744]

[0745] With reference 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 (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 10.57 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.59–7.51 (m, 1H), 7.47 (s, 1H), 7.38–7.29 (m, 2H), 7.18–7.08 (m, 2H), 6.82 (s, 1H), 5.01 (s, 1H), 3.95 (s, 3H), 3.89 (t, J = 6.7 Hz, 2H), 3.71 (s, 3H), 3.60–3.48 (m, 1H), 3.19 (d, J = 11.0 Hz, 3H), 3.08 (t, J = 11.0 Hz, 3H), 2.85 (d, J = 13.2 Hz, 4H), 2.74 (t, J = 6.7 Hz, 2H), 2.60 (dd, J = 15.8, 8.3 Hz, 5H), 2.00 (q, J = 7.8 Hz, 2H), 1.84 (d, J = 11.2 Hz, 2H), 1.77 (d, J = 13.6 Hz, 8H), 1.08 (t, J = 7.5 Hz, 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] 500 mg of SM1, 558 mg of boc piperazine, and 552 mg of potassium carbonate were added to a 100 ml single-necked flask and dissolved in 10 ml of 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 concentrated by rotary evaporation and then purified by column chromatography to obtain 760 mg of Compound 2.

[0755] Synthesis of Compound 3

[0756] In a 100 ml single-necked flask, 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. After mixing, the mixture was purged with a carbon monoxide balloon three times, sealed with a balloon, and reacted at 85 °C overnight. After the reaction was completed as detected by TLC, the reaction solution was extracted with ethyl acetate and water. The organic phases were combined, dried, and concentrated by evaporation. Column chromatography was performed 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-necked flask, 150 mg of Compound 3, 10 mg of palladium on carbon, and 3 ml of methanol were added. After mixing, the mixture was reacted at 35 °C overnight. After the reaction was completed, it was filtered through a diatomaceous earth pad, and the mother liquor was collected and concentrated by evaporation to obtain crude Compound 4.

[0759] Synthesis of Intermediate M1

[0760] In a 100 ml single-necked flask, 112 mg of intermediate pyrimidine, 130 mg of Compound 4, 87 mg of p-toluenesulfonic acid monohydrate, and 4 ml of isopropanol were added, and the temperature was raised to 90 °C and reacted overnight. After the reaction was completed, it was purified by column chromatography to obtain 60 mg of Intermediate M1.

[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 (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.60 (s, 1H), 8.40 (s, 2H), 8.11 (s, 1H), 7.94 (s, 1H), 7.71 (d, J = 5.6 Hz, 1H), 7.49–7.37 (m, 2H), 7.23 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 3.97 (s, 3H), 3.91 (t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 3.73 (s, 6H), 3.59 (s, 2H), 3.15–2.94 (m, 6H), 2.84–2.66 (m, 4H), 2.39 (d, J = 12.5 Hz, 2H), 2.00 (d, J = 8.2 Hz, 1H), 1.85 (s, 1H), 1.76 (d, J = 13.4 Hz, 6H)

[0765] With reference to the synthesis methods of intermediate compound M1 and 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. After dissolving 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 overnight at room temperature. After detecting the completion of the reaction by TLC, add water to the reaction solution and extract with ethyl acetate. The organic phase is washed twice with saturated brine, dried and concentrated, and purified by column chromatography to obtain 10 mg of compound TC-135. LC-MS [M+1]: 949.8 HPLC: 95.49%

[0773] 11H NMR (400 MHz, DMSO) δ 11.22 (s, 1H), 10.59 (s, 1H), 8.50 (s, 2H), 8.09 (s, 1H), 7.68 (d, J = 4.6 Hz, 1H), 7.48 (dd, J = 14.2, 8.3 Hz, 1H), 7.44 (d, J = 10.4 Hz, 1H), 7.27 (s, 1H), 7.10–7.00 (m, 2H), 4.42 (s, 2H), 4.12 (dd, J = 10.5, 5.2 Hz, 1H), 3.98 (s, 2H), 3.92 (t, J = 6.8 Hz, 2H), 3.57 (t, J = 6.4 Hz, 1H), 3.50 (s, 1H), 3.46 (s, 1H), 3.29–3.26 (m, 1H), 3.25 (s, 1H), 3.17 (d, J = 5.2 Hz, 2H), 3.06 (d, J = 9.7 Hz, 2H), 2.93 (s, 3H), 2.82–2.69 (m, 3H), 2.62 (dd, J = 14.8, 7.5 Hz, 2H), 2.53 (s, 1H), 2.43–2.31 (m, 2H), 2.12–1.94 (m, 1H), 1.88 (s, 1H), 1.76 (d, J = 13.5 Hz, 5H), 1.24 (s, 1H), 1.12 (t, J = 7.4 Hz, 3H), 0.85 (d, J = 6.8 Hz, 1H).

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

[0775]

[0776] Synthesis of Compound TC-144

[0777]

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

[0779] LC-MS [M+1]: 957.7 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.60 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 7.61–7.43 (m, 4H), 7.36 (s, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.83 (s, 1H), 5.16 (s, 2H), 4.03 (d, J = 6.0 Hz, 4H), 3.93 (t, J = 6.6 Hz, 2H), 3.77 (s, 9H), 2.88 (d, J = 25.6 Hz, 5H), 2.77 (t, J = 6.7 Hz, 2H), 2.58 (d, J = 7.4 Hz, 3H), 2.11 (d, J = 10.1 Hz, 6H), 1.99 (s, 2H), 1.76 (d, J = 13.5 Hz, 6H), 1.17 (t, J = 7.1 Hz, 2H), 1.06 (t, J = 7.4 Hz, 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 (400 MHz, DMSO-d6) δ 10.86 (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, 1H), 4.05 (t, J = 6.7 Hz, 2H), 3.69 (d, J = 17.4 Hz, 9H), 3.03 (d, J = 10.7 Hz, 2H), 2.94–2.70 (m, 8H), 2.31–2.10 (m, 3H), 1.93 (s, 2H), 1.74 (d, J = 13.5 Hz, 6H), 1.06 (t, J = 7.4 Hz, 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 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 10.58 (s, 1H), 8.42 (s, 1H), 8.15 (d, J = 31.0 Hz, 2H), 7.54 (dd, J = 30.8, 20.5 Hz, 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 = 7.5 Hz, 2H), 3.23 (s, 2H), 3.03 (s, 1H), 2.91 (s, 2H), 2.79 (d, J = 27.0 Hz, 3H), 2.65 (d, J = 7.7 Hz, 1H), 2.61 (d, J = 6.7 Hz, 2H), 2.27 (d, J = 11.1 Hz, 1H), 1.99 (s, 1H), 1.89 (s, 1H), 1.76 (d, J = 13.3 Hz, 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 synthesis route is as follows:

[0797]

[0798] 1. Synthesis of Compound 2

[0799] Weigh 600 mg of 1 and dissolve it in 6 mL of DMF in a 50 mL three-necked flask. Then add 188 mg of A1 and 469 mg of DIPEA. After purging with N2 three times, react at 90 °C overnight. Monitor the reaction by TLC. When a new spot appears, add water to the reaction solution, extract with ethyl acetate, dry with anhydrous sodium sulfate, and perform column chromatography to obtain 448 mg of Compound 2.

[0800] 2. Synthesis of Intermediate 3

[0801] Dissolve 448 mg of Compound 2 and 252 mg of DIPEA in 5 mL of DCM in a 50 mL single-necked flask. Dissolve 206 mg of A2 in 2 mL of DCM and slowly add it dropwise to the reaction solution. After purging with N2 three times, react at room temperature for 2 h. Monitor the reaction by TLC until Compound 2 no longer decreases. Directly concentrate the reaction solution under reduced pressure, mix the sample, and perform column chromatography to obtain 286 mg of Intermediate 3.

[0802] Synthesis of Compound TC-099

[0803] The synthesis route is as follows:

[0804]

[0805] Dissolve 186 mg of Compound M3 and 119 mg of the starting amine (Compound 3 in INT-17) in 3 mL of acetonitrile in a 50 mL round-bottom flask. Then add 82 mg of KI and 159 mg of DIPEA. After purging with N2 three times, react at 75 °C for 3 h. Detect the completion of the reaction by TLC. Concentrate the reaction solution under reduced pressure, mix the sample, and perform column chromatography to obtain 190 mg of Compound TC-099.

[0806] LC-MS [M+1]: 922.7. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 10.61 (s, 1H), 8.44 (s, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.55 (dd, J = 14.1, 7.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 7.32 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (s, 1H), 4.03 (s, 3H), 3.92 (t, J = 6.6 Hz, 2H), 3.77 (s, 3H), 3.12 (s, 2H), 2.86 (d, J = 5.6 Hz, 4H), 2.76 (t, J = 6.7 Hz, 3H), 2.71–2.63 (m, 4H), 2.37 (s, 3H), 1.77 (d, J = 13.5 Hz, 7H), 1.07 (t, J = 7.5 Hz, 3H)

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

[0808]

[0809] The synthesis method refers to HISCO 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 of SM1, 10.7 g of vinyl boron trifluoride, 2.9 g of pd(dppf)Cl2, and 8.2 g of potassium carbonate were dissolved in 50 mL of 1,4-dioxane and 10 mL of H2O. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction solution was cooled to room temperature, and the insoluble impurities were removed by suction filtration. The filtrate was added with water and extracted with EA. The organic phase was washed once with saturated NaCl and then dried, directly rotary evaporated and mixed with samples, and 14.4 g of compound 2 was obtained by column chromatography. 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. After protecting with N2 gas, the temperature was raised to 100 °C and the reaction was carried out overnight. TLC showed that the raw materials disappeared. The reaction solution was cooled to room temperature, and the insoluble impurities were removed by suction filtration. The filtrate was added with water and extracted with EA. The organic phase was washed once with saturated NaCl and then dried, directly rotary evaporated and mixed with samples, 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 reaction kettle, 3.8 g of compound 3 and 1.5 g of palladium carbon were dissolved in 35 mL of methanol. After protecting with H2 gas, the reaction was carried out at room temperature overnight. TLC showed that the raw materials disappeared. The reaction solution was filtered to remove the insoluble impurities by suction, and the filtrate was directly rotary evaporated and mixed with samples, and 2.9 g of compound 4 was obtained by column chromatography. 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. After protecting with N2 gas, the temperature was raised to 90 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction was quenched with a small amount of saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, rotary evaporated, and 331 mg of intermediate M1 was obtained by column chromatography. LC-MS [M+1]: 496.

[0825] Synthesis of intermediate compound M2

[0826] The synthesis route is as follows:

[0827]

[0828] 1. Synthesis of compound 2a

[0829] In a 50 ml three-necked flask, 220 mg of compound 1a (1.0 equivalent), 67 mg of bromoethanol (1.2 equivalents), 172 mg of DIPEA (3.0 equivalents), and 5 ml of DMF were mixed evenly and refluxed at 90 °C overnight. The reaction was monitored by TLC (DCM:MEOH = 10:1) until completion. The reaction solution was cooled to room temperature and diluted with EA (5 ml). It was extracted 3 times with 15 ml of ethyl acetate. The combined organic phases were mixed with sample and passed through a column. Column chromatography gave 140 mg of compound 2a.

[0830] 2. Synthesis of Compound M2

[0831] In a 50 ml single-necked flask, 140 mg of compound 2a, 99 mg (2.0 eq) of TosCl, and 79 mg (3.0 eq) of triethylamine were dissolved in 2.8 ml of DCM. The mixture was stirred at room temperature for 16 h. The solvent was removed by rotary evaporation, and column chromatography gave 60 mg of compound M2.

[0832] Synthesis of Intermediate M3

[0833] The synthesis route is as follows:

[0834]

[0835] 1. Synthesis of Compound 2b

[0836] In a 50 ml single-necked flask, 300 mg of compound 1b (1.0 equivalent), 272 mg of SM2 (1.0 equivalent), 280 mg of sodium carbonate (1.5 equivalents), 6 ml of 1,4-dioxane, and 1.5 ml of water were mixed evenly under nitrogen protection. 63 mg of [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (0.1 equivalent) was added again. The nitrogen was replaced three times and the temperature was raised to 100 °C, and the reaction was carried out overnight. The reaction was monitored by TLC until completion, filtered through a diatomaceous earth pad, and the mother liquor was collected. The solvent in the mother liquor was removed by rotary evaporation, 30 ml of water was added, and it was extracted 3 times with 15 ml of ethyl acetate. The combined organic phases were mixed with sample and passed through a column. Column chromatography gave 345 mg of compound 2b.

[0837] 2. Synthesis of Compound 3b

[0838] In a 50 ml single-necked flask, 345 mg of compound 2b and 34.5 mg of Pd / C were added to 3.4 ml of MeOH. The 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 solvent in the filtrate was removed by rotary evaporation to obtain 345 mg of compound 3b. LC-MS [M+1]: 446.

[0839] 3. Synthesis of Compound M3

[0840] In a 50 ml single-necked flask, 345 mg of compound 3b and 2 ml of hydrochloric acid dioxane solution were added to 3 ml of THF, and the reaction was carried out 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, then 17.2 mg of KI and 33 mg of DIPEA were added. After purging with N2 three times, the reaction was carried out at 75 °C for 16 h. TLC detected that the reaction was complete. The reaction solution was concentrated under reduced pressure, mixed with samples, and purified by column chromatography to obtain 33 mg of the compound.

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

[0846] 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 10.58 (s, 1H), 8.77 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 5.9 Hz, 1H), 7.48 (s, 1H), 7.39 (d, J = 10.9 Hz, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.81 (s, 1H), 4.01 (s, 3H), 3.91 (t, J = 6.7 Hz, 2H), 3.77 (s, 3H), 2.90 (s, 4H), 2.83–2.72 (m, 5H), 2.58 (q, J = 7.6 Hz, 1H), 1.90 (s, 4H), 1.24 (d, J = 8.0 Hz, 4H), 1.08 (t, J = 7.5 Hz, 3H).

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

[0848]

[0849] Control Example 3-1: Synthesis of compound C1

[0850] The synthetic route is as follows:

[0851]

[0852] In a 50 ml round-bottom flask, compound M2 (150 mg, 1.0 eq) and M1 (176 mg, 1.0 eq) were dissolved in 4 ml of N,N-dimethylformamide. The temperature was lowered to 0 °C in an ice-water bath. Under stirring, N,N-diisopropylethylamine and HATU (176 mg, 1.3 eq) were added. The reaction was carried out in an ice-water bath for 1 hour under nitrogen protection, and then naturally warmed to room temperature. The reaction was detected by TLC to be complete. It was extracted with ethyl acetate and water. The organic phase was dried, filtered, and then purified by column chromatography to obtain 90 mg of the reference compound C1. LC-MS [M+1]: 899.6.

[0853] 1H NMR (400 MHz, DMSO-d6) δ 11.69 (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 = 7.8 Hz, 1H), 7.71–7.52 (m, 3H), 7.38 (s, 1H), 7.13 (q, J = 8.5, 7.6 Hz, 2H), 6.88 (s, 1H), 4.12–3.93 (m, 6H), 3.79 (d, J = 18.4 Hz, 5H), 3.68 (s, 3H), 3.53–3.51 (m, 1H), 3.20 (d, J = 7.6 Hz, 2H), 3.10 (s, 1H), 2.98 (s, 2H), 2.93–2.78 (m, 8H), 2.69 (d, J = 7.4 Hz, 1H), 2.33 (d, J = 12.9 Hz, 1H), 2.05 (s, 1H), 1.94 (d, J = 13.0 Hz, 1H), 1.16 (t, J = 7.6 Hz, 3H).

[0854] Test of the inhibitory activity of the compound on cell growth

[0855] Test Example 1: Cell Anti-Proliferation Experiment

[0856] I. Experimental materials and equipment:

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

[0858] II. Experiment Preparation:

[0859] 1. Plating 96-well plates

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

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

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

[0863] 2. Compound treatment

[0864] Compound dilution

[0865] A) Weigh approximately 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) Place the inoculated cell culture plate in the incubator for cultivation, and add compounds with a concentration gradient after about 24 hours.

[0867] C) Dilute the 10 mM compound stock solution with the culture medium to 50 mM, and sequentially add the 50 mM compound solution to the second column of the deep well plate, and add 375 μl of the culture medium containing 0.5% DMSO to the third to eleventh columns.

[0868] D) Serial dilution: Pipette 125 μl of the solution from the second column into the third column, and after mixing; then pipette 125 μl of the solution from the third column into the fourth column, and repeat this operation until the tenth column.

[0869] E) Use a multi-channel pipette to pipette 25 μl of the compound from the deep well plate into a 96-well culture plate, and repeat each compound three times on the 96-well plate. Finally, a concentration gradient with a maximum concentration of 10000 nM and a 1:4 ratio is formed on the 96-well plate.

[0870] 3. Add CTG and read the values

[0871] A) Incubate the 96-well plate in the incubator for 72 hours, and observe the effect of the compound under an inverted microscope.

[0872] B) Add 25 μl of the CTG solution to each well, place it on a shaker for 10 minutes, and read the OD value of each well.

[0873] 4. Data analysis

[0874] Calculate the cell viability (%) using the following formula:

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

[0876] Lum_HC: Cell reading of the 0.1% DMSO control group

[0877] Lum_Sample: Cell reading with the compound added

[0878] Lum_LC: Reading of the blank culture medium

[0879] Obtain the IC50 value by curve fitting using GraphPad Prism 8 software.

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

[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 the inhibitory effect on cells with exon 19 deletion is second. The inhibitory effect on wild-type EGFR is not obvious.

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

[0886] 1) Comparing TA-023 with TC-157 shows that in the selection of ring B, the use of a spiro structure has better inhibitory activity against the L858 mutation than the piperazine ring, and the inhibition of wild-type EGFR is improved;

[0887] 2) Comparing TC-225 with TA-023 shows that when the position of the spiro ring changes, the inhibition of mutant EGFR will also decrease;

[0888] 3) Comparing TC-213 and TC-215 with TC-157 shows that when a fluorine atom is added at a specific position, the inhibitory effect on EGFR can be increased and the inhibition of wild-type EGFR can be reduced;

[0889] 4) Comparing TC-185 with TC-157 shows that when a cyclic oxygen phosphorus structure is used instead of the dimethyl phosphorus structure, the selectivity for wild-type EGFR can be improved;

[0890] 5) Comparing TB-006 with DZL-1 (Control Example 2-1) shows that TB-006 has better inhibitory effects on H1975, BaF3-LTC and BaF3-DTC.

[0891] 6) Comparing TA-023 with Control Example 2-2 shows that the use of the new E3 and spiro ring structure has better inhibitory activity against the L858 mutation than the original structure, and has higher selectivity for wild-type EGFR.

[0892] Test Example 2: EGFR PROTAC HTRF Experiment

[0893] 1. Instruments and Reagents

[0894]

[0895]

[0896] Among them, Baf3-19del-T790M-C797S (abbreviated as Baf3-DTC) is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing T790M, C797S and L858R triple amino acid mutations, purchased from Kangyuan Bochuang. Baf3-L858R-T790M-C797S (abbreviated as Baf3-LTC) is a Stable Ba / F3 clone expressing exogenous EGFR gene bearing exon19 E746_A750 deletion, T790M, C797S triple mutations, purchased from Kangyuan Bochuang.

[0897] 2. Experimental procedures

[0898] 1) Cell preparation:

[0899]

[0900] 2) Reagent preparation:

[0901]

[0902] Dilute Eu and d2 antibody 20-fold 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] The fitted curve, DC50 and Dmax of the compound can be generated using GraphPad Prism.

[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: Pharmacokinetics 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 housed in rat cages and fasted (for at least 10 h) starting from the day before the experiment, but water was not restricted. On the day of the experiment, they were weighed separately and marked on the tail. Blank blood samples were collected before drug administration. The blood collection method was tail vein blood collection.

[0929] 3.3.3. Drug Administration

[0930] Route of drug administration: intragastric administration (p.o.);

[0931] Drug concentration: 1 mg / ml;

[0932] Drug dose: 10 mg / kg;

[0933] Drug volume: 10 mL / kg;

[0934] Operation procedure: Grasp the rat with the left hand wearing bite-resistant gloves to make it stand upright. Insert the gavage needle into the throat through the mouth. When no obvious resistance is felt during probing, insert the needle further and then inject the drug into the stomach.

[0935] 3.4. Sample Collection

[0936] Whole blood (0.1 - 0.2 ml) was collected from the test animals at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after drug administration into EDTA-Na2 anticoagulant tubes. The tubes were inverted 3 - 4 times to mix evenly. The samples were centrifuged at 4°C and 2000 g for 5 min to separate the upper plasma, which was immediately transferred to -80°C for storage until analysis. The blood collection method was tail vein blood collection.

[0937] 3.5. Sample Analysis and Data Processing

[0938] 3.5.1. Sample Analysis

[0939] A quantitative detection method for the compound to be tested was established using a Shimadzu liquid phase and a Triple Quad TM 6500 + AB mass spectrometer. The concentration of the parent drug in the 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% - 120%.

[0940] 3.5.2. Data Processing

[0941] The non-compartmental model in the 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 the maximum plasma concentration (T max ), etc.

[0942] The results are shown in Table 3.

[0943] Table 3

[0944]

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

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

[0947] 4.1. Experimental purpose

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

[0949] 4.2. Information on test articles and reference standards

[0950] Calculation formula for the conversion factor of free base: Conversion factor CF = (MW / FW) * purity.

[0951] 4.3. Preparation of formulations

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

[0953] Process of preparing the formulation: Weigh the compound powder accurately, add appropriate volumes of DMSO, Solutol and normal saline in sequence, and vortex and ultrasonicate each step to finally form a homogeneous formulation solution.

[0954] Two samples of the formulation were retained before dosing and the remaining formulation after dosing, and stored at 2 - 8 °C for shipment.

[0955] 4.4. Experimental animals

[0956] The experimental animals were housed in the SPF-class animal facility of Suzhou Xihua New Drug Development Co., Ltd. (Use license number: SYXK (Su) 2021-0019). After the animals were purchased, they were fed normally for at least 3 days before the experiment, and each mouse was marked with a tail label. The animals in the oral administration group were fasted overnight before dosing and resumed feeding 4 hours after dosing, and had free access to water. The sources and numbers of the animals used in this experiment are shown in Table 4.

[0957] Table 4 Sources and numbers of experimental animals

[0958]

[0959] 4.5. Experimental design

[0960] 1) Free access to water was available before and after dosing;

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

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

[0963] Before administration, check the status of the administered preparation, and ensure the uniformity of the preparation by vortexing, stirring or oscillating. 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] Remarks:

[0970] 1) The blood sampling time window for blood sampling points within 1 hour (excluding the blood sampling point before administration) is ±1 minute, and the blood sampling time window for other time points is ±5%; 2) The samples are sent out for testing.

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

[0972] 4.7. Experimental observation

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

[0974] 4.8. Sample analysis and data processing

[0975] 4.8.1. Sample analysis

[0976] Establish a quantitative detection method for the compound to be tested using Shimadzu liquid phase and Triple Quad TM 6500+AB mass spectrometry. Analyze the concentration of the prototype drug in plasma. The analysis results are controlled for variation using quality control samples, and the accuracy of the quality control samples should be between 80% - 120%.

[0977] 4.8.2. Data processing

[0978] The main pharmacokinetic parameters were calculated using the non-compartmental model in Winnolin Phoenix software, including the area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞)), elimination half-life (T1 / 2), maximum plasma concentration (Cmax), time to reach the maximum plasma concentration (Tmax), etc.

[0979] The results are shown in Table 6.

[0980] Table 6

[0981]

[0982] It can be seen from Table 6 that the compounds of the present invention have excellent pharmacokinetic effects. Compared with Control Example 1-1, they have higher exposure and better pharmacokinetic effects.

[0983] All the documents mentioned in the present invention are cited in this application as references, just as if each document was individually cited as a reference. 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 appended claims of this application.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein, X3 is NH; X2 is NR; Each R is independently selected from C 1-6 alkyl, halo C 1-6 alkyl; X1 is N; X4 is CH; Ring B selected from the group consisting of: substituted or unsubstituted 6- to 7-membered heteroarylene groups, substituted or unsubstituted 7- to 9-membered heterospiro groups; said substitution is such that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, C 1-6 alkyl, halo C 1-6 alkyl; Ring A is selected from the group consisting of: substituted C 6-10 aryl, substituted 6- to 10-membered heteroaryl; said substitution means that one hydrogen on the group is replaced by R6; wherein, R6 is selected from the group consisting of: -P(O)RaRb, -C(O)R, -C(O)NHR, -C(O)NRaRb, -S(O)2R, -NR-S(O)2R; Ra and Rb are each independently C 1-6 alkyl, or Ra and Rb together with the heteroatom to which they are commonly attached form a 5- to 7-membered heterocycle; R1 is selected from halogen; R2 is selected from H, unsubstituted C 1-6 alkyl; R3 is selected from halogen; each R4 is independently halogen; Each R5 is independently H, C 1-6 alkyl; R8 is selected from: C 1-6 alkyl, halo-C 1-6 alkyl.

2. A compound, characterized in that, the compound is a compound of formula II or a pharmaceutically acceptable salt thereof, wherein, X3 is NH; X2 is NR; Each R is independently C 1-6 alkyl; X1 is N; X 11 is N; X4 is CR'; X5 is CH; X 51 is N; Ring B selected from the group consisting of: substituted or unsubstituted 6- to 7-membered hetero monocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 7- to 9-membered hetero bridged cyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O, or S, substituted or unsubstituted 7- to 10-membered hetero spirocyclic alkyl groups; said substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, C 1-6 alkyl, halo C 1-6 alkyl; Ring C Selected from the group consisting of: substituted or unsubstituted 6- to 7-membered hetero monocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O or S, substituted or unsubstituted 7- to 9-membered hetero spirocyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O or S, substituted or unsubstituted 4- to 10-membered hetero bridged cyclic alkyl groups containing 1 to 3 heteroatoms selected from N, O or S; said substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, C 1-6 alkyl, halo C 1-6 alkyl; Ring A is selected from the group consisting of: substituted C 6-10 aryl, substituted 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O or S; said substitution means that one hydrogen on the group is replaced by R6; R6 is selected from the group consisting of: -P(O)RaRb, -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; R1 is halogen; R2 is C 1-6 alkyl; R3 is halogen; R4 is H; R5 is H; R8 is selected from the group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl; L is selected from the following group: Each R' is independently selected from the group consisting of: H, C 1-6 alkyl; n is selected from the group consisting of: 1, 2; n1 is selected from the group consisting of: 0, 1, 2; m1 is selected from the group consisting of: 0, 1, 2.

3. A compound of formula III or a pharmaceutically acceptable salt thereof, wherein, X1 and X5 are each independently selected from CH, N, C; X2 is NR; X3 is NH; X4, X6 and X7 are each independently CR; Each R is independently selected from the group consisting of: H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, C 3-7 cycloalkyl, C 3-7 cycloalkoxy, C 6-10 aryl; L is m and n are each independently 0, 1, 2, 3 or 4; R7, R8 together with the P to which they are attached form Cy1, Cy1 is selected from the group consisting of: a saturated or partially unsaturated 4-7 membered ring containing P=O, the ring containing, in addition to P, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R7 and R8 are each independently selected from the group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl; R1 is selected from halogen; R2 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -(C=O)-O-C 1-6 alkyl, -(C=O)-NH-C 1-6 alkyl, halogen, C 1-6 a 5- or 6-membered heteroaryl group which is alkyl-substituted or unsubstituted and contains 1 to 3 heteroatoms selected from N, O or S; R3 is halogen; R4 is H; R5 is H; R6 is selected from the group consisting of: C 1-6 alkyl, halo-C 1-6 alkyl; or, X4 is CR, and the R of X4 is connected to R6 to form a saturated or partially saturated 5- or 6-membered heterocyclic group containing 1 O; Ring B selected from the group consisting of: substituted or unsubstituted 6- to 7-membered heteroarylene groups, substituted or unsubstituted 7- to 12-membered heterospiro groups, substituted or unsubstituted 7- to 12-membered heterobicyclic groups; said substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: D, halogen, C 1-6 alkyl, halo C 1-6 alkyl; Ring C selected from the group consisting of: a substituted or unsubstituted 6- to 7-membered heteroarylene group, a substituted or unsubstituted 5- to 6-membered heteroaryl group, or a substituted or unsubstituted 7- to 12-membered heterospiro group; said substitution means that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, C 1-6 alkyl, halo-C 1-6 alkyl; Among them, each of the said heteroarylene group, heteroaryl group, heterospiro group, heterobicyclic group independently contains 1-3 heteroatoms selected from N, S and O.

4. The compound according to claim 3, characterized in that, Ring B selected from the group consisting of a substituted or unsubstituted 6- to 7-membered heteroarylene group, or a substituted or unsubstituted 7- to 10-membered heterospiro group.

5. The compound according to claim 3, wherein, 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 substituted by substituents selected from the following group: halogen, C 1-6 alkyl, halo-C 1-6 alkyl.

6. The compound according to claim 3, wherein, Ring C is a substituted or unsubstituted group selected from the group consisting of: a 6- to 7-membered heteroarylene group, a 5- to 6-membered heteroaryl group, or a 7- to 10-membered heterospiro group.

7. The compound according to claim 3, wherein Ring C is a substituted or unsubstituted group selected from the group consisting of: wherein said substitution is that one or more hydrogens on the group are substituted by substituents selected from the group consisting of: halogen, C 1-6 alkyl, halo-C 1-6 alkyl; R a 、R b and R are as described in claim 3.

8. The compound according to claim 3, characterized in that, The said compound has the structure shown in formula 2: wherein, R' and R” are each independently selected from the group consisting of: D, halogen, C 1-6 alkyl, halo C 1-6 alkyl; m, n are each independently selected from the group consisting of: 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.

9. A compound or a pharmaceutically acceptable salt thereof, characterized in that, The said compound is selected from the group consisting of:

10. A pharmaceutical composition, characterized by comprising (a) a therapeutically effective amount of the compound according to claim 1 or 2 or 3 or 9 as an active ingredient, and (b) a pharmaceutically acceptable carrier.

11. Use of a compound according to claim 1 or 2 or 3 or 9, characterized in that, For use in the following uses: 1) Preparing a drug for regulating abnormal EGFR kinase activity; 2) Preparing a drug for preventing and / or treating diseases associated with abnormal or mutated EGFR kinase activity; and / or 3) Preparing a drug for degrading EGFR protein.

12. The use according to claim 11, characterized in that, The said diseases associated with abnormal or mutated EGFR kinase activity are selected from the group consisting of: inflammation, cancer, cardiovascular diseases, infections, immune diseases, metabolic diseases, or a combination thereof.

13. The use according to claim 11, wherein, The said diseases associated with abnormal or mutated EGFR kinase activity are diseases associated with EGFR drug-resistant mutations.

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