Compounds inhibiting egfr kinase and uses thereof

Abstract

The application discloses a compound shown in a general formula (I), wherein when A is S, m=0 or 2, n=1; when A is P, m=1, n=2; Y is N or CH; when Z is NH, Q1 and Q2 are C respectively; when Z is a connecting bond, Q1 is N, R4Q2 is a connecting bond, R2 and R3 are linked together to form a C6-C10 aryl group which is unsubstituted or substituted by 1-3 R'', or a 5-6 membered heteroaryl group containing 1-2 optional N, O, S heteroatoms. The compound of the general formula (I) has good inhibitory activity on C797S drug resistance mutations appearing on an EGFR gene.

Description

Technical Field

[0001] This invention belongs to the field of small molecule compound synthesis technology, specifically relating to a compound that inhibits EGFR kinase and its applications. Background Technology

[0002] A century ago, lung cancer was considered a rare disease in the medical field. A century later, non-small cell lung cancer (NSCLC) has become the leading cause of cancer-related morbidity and mortality in many parts of the world. Patients with epidermal growth factor receptor (EGFR) gene mutations account for a very high percentage (20-40%) of NSCLC cases, making each generation of EGFR-targeted inhibitors a highly anticipated breakthrough in clinical trials and the market. The advent of third-generation EGFR inhibitors finally fundamentally solved the problem of EGFR-T790M resistance mutations. However, how to address the C797S resistance mutation in the EGFR gene that accompanies third-generation drugs remains a challenge. Currently, investigational drugs in Phase I clinical trials include BLU-701, BLU-945, BDTX-1535, BAY2927088, and TQB3804. It is hoped that these drugs will become the fourth generation of EGFR-targeted inhibitors that can overcome the C797S resistance mutation. They can not only overcome the two major common triple mutations caused by resistance to third-generation inhibitors, but also inhibit EGFR wild-type mutations and T790M mutations caused by the first two generations of targeted drugs. Summary of the Invention

[0003] The purpose of this invention is to provide a compound of general formula (I), or its stereoisomers, racemates, tautomers, isotope-labeled forms, nitrogen oxides, solvates, hydrates, or pharmaceutically acceptable salts thereof.

[0004]

[0005] When A is S, m = 0 or 2, n = 1;

[0006] When A is P, m = 1, n = 2;

[0007] Y is either N or CH;

[0008] When Z is NH, Q1 and Q2 are C respectively;

[0009] When Z is the linking bond, Q1 is N, R4Q2 is the linking bond, and R2 and R3 are linked together to form an unsubstituted or 1-3 R" substituted C6-C10 aryl group or a 5-6 membered heteroaryl group containing 1-2 selected N, O, S heteroatoms;

[0010] R1 can be H, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkoxy, borate C1-C6 alkyl, borate C2-C6 alkenyl, borate C2-C6 alkynyl, borate C3-C10 cycloalkyl, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C3-C10 cycloalkyl, hydroxyl C1-C6 alkyl, hydroxyl C2-C6 alkenyl, hydroxyl C2-C6 Alkynyl, hydroxyl C3-C10 cycloalkyl, C1-C6 alkylamino, C2-C6 enamino, C2-C6 alkynamino, C3-C10 cycloalkylamino, C1-C6 amino C1-C6 alkyl, C1-C6 amino C2-C6 alkenyl, C1-C6 amino C2-C6 alkynyl, C1-C6 amino C3-C10 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C2-C6 alkenyl, C1-C6 alkoxy C2-C6 alkynyl, C1-C6 alkoxy C3-C10 cycloalkyl, C1-C6 aldehyde, C1-C6 carbonyl, C1-C6 carboxyl, R 11 ON=CR 11 -、R 11 C(O)NR 11 - Unsubstituted or substituted with 1 to 3 R” C6 to C10 aryl groups, unsubstituted or substituted with 1 to 3 R” C2 to C8 heteroaryl groups containing 1 to 3 heteroatoms selected from N, O or S, or unsubstituted or substituted with 1 to 3 R” C2 to C8 heterocyclic groups containing 1 to 3 heteroatoms selected from N, O or S;

[0011] Each of R2, R3, R4, and R5 is independently H, halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkoxy, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl, halo-C3-C10 cycloalkyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, hydroxy-C2-C6 alkynyl, hydroxy-C3-C10 cycloalkyl, C1 -C6 alkylamine, C2-C6 enamine, C2-C6 alkynamine, C3-C10 cycloalkylamine, C1-C6 amino C1-C6 alkyl, C1-C6 amino C2-C6 alkenyl, C1-C6 amino C2-C6 alkynyl, C1-C6 amino C3-C10 cycloalkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkoxy C2-C6 alkenyl, C1-C6 alkoxy C2-C6 alkynyl, C1-C6 alkoxy C3-C10 cycloalkyl, C1-C6 aldehyde, C1-C6 carbonyl, or C1-C6 carboxyl;

[0012] Alternatively, R1 and R3 can be linked together to form -NR. 11 -or-C(O)NR 11 -;

[0013] Alternatively, R4 and R5 can be linked together to form unsubstituted or substituted C1-C4 alkane chains or C2-C4 alkene chains;

[0014] R N1 R Y1 R Y2 Independently, it is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkenyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C1-C6 alkoxy, halo-C1-C6 alkenyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, C1-C6 alkoxy-C1-C6 alkyl, NH2-C1-C6 alkylene, (C1-C6 alkyl)NH(C1-C6 alkylene)-, (C1-C6 alkyl)2N(C1-C6 alkylene)- or (R N2 )2N-;R N2 Independently, it is H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, halo-C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked to 1 to 10 R's;

[0015] Or R N1 and R Y1 They covalently form C1-C4 alkyl chains or C2-C4 olefin chains with 1-3 R's;

[0016] Each R' is independently H, halogen, CN, OH, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkenyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C1-C6 alkoxy, halo-C1-C6 alkenyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, C1-C6 alkoxy-C1-C6 alkyl, NH2C1-C6 alkylene, (C1-C6 alkyl)NH(C1-C6 alkylene)-, (C1-C6 alkyl)2N(C1-C6 alkylene)-, or (C1-C6 alkyl)2N-;

[0017] Alternatively, two R's on the same ring can covalently form an unsubstituted C1-C4 alkane chain or a C2-C4 alkene chain, or one to three R's that are substituted.

[0018] Among them, R 11Independently, it is H, C1-C6 alkyl, C1-C6 alkenyl, hydroxy C1-C6 alkyl, or C1-C4 alkoxy C1-C6 alkyl;

[0019] R” can be independently a halogen, CN, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkenyl, halo-C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C1-C6 alkoxy, halo-C1-C6 alkenyl, hydroxy-C1-C6 alkyl, hydroxy-C2-C6 alkenyl, C1-C6 alkoxy-C1-C6 alkyl, NH2-C1-C6 alkylene, (C1-C6 alkyl)NH-, (C1-C6 alkyl)2N- or, (C1-C6 alkyl)NH(C1-C6 alkylene)-, or (C1-C6 alkyl)2N(C1-C6 alkylene)-.

[0020] In a preferred embodiment of the present invention

[0021] When Z is the linking bond, Q1 is N, R4Q2 is the linking bond, and R2 and R3 are linked together to form a benzene ring. Then, general formula (Ⅰ) becomes general formula (Ⅰa) as follows.

[0022]

[0023] In a preferred embodiment of the present invention

[0024] When Z is NH, Q1 and Q2 are C, respectively.

[0025] Then general formula (Ⅰ) takes the form of general formula (Ⅰb),

[0026]

[0027] In a preferred embodiment of the present invention

[0028] When R N1 and R Y1 Together they form a C2 alkyl chain with two R's.

[0029] Then general formula (Ⅰ) takes the form of general formula (Ⅰc).

[0030]

[0031] In a preferred embodiment of the present invention

[0032] When Y is CH, R Y2 For (R) N2 When 2N-, general formula (Ⅰc) is transformed into general formula (Ⅰd).

[0033]

[0034] In a preferred embodiment of the present invention

[0035] When two R N2 When combined with N, it forms a six-membered heteroalkyl ring with five R' atoms and two N atoms, thus formula (Id) becomes formula (Ie).

[0036]

[0037] In a preferred embodiment of the present invention

[0038] When Z is the linking bond, Q1 is N, R4Q2 is the linking bond, and R2 and R3 are linked together to form a benzene ring. Then, general formula (Ⅰc) becomes general formula (Ⅰf).

[0039]

[0040] In a preferred embodiment of the present invention

[0041] When Z is NH, Q1 and Q2 are C, respectively.

[0042] Then the general formula (Ⅰc) takes the form of the following general formula (Ⅰg).

[0043]

[0044] In a preferred embodiment of the present invention

[0045] When Z is the linking bond, Q1 is N, R4Q2 is the linking bond, and R2 and R3 are linked together to form a benzene ring. Then, the general formula (Ⅰd) becomes the following general formula (Ⅰh).

[0046]

[0047] In a preferred embodiment of the present invention

[0048] When Z is NH, Q1 and Q2 are C, respectively.

[0049] Then the general formula (Ⅰd) takes the form of the following general formula (Ⅰi),

[0050]

[0051] In a preferred embodiment of the present invention

[0052] When Z is the linking bond, Q1 is N, R4Q2 is the linking bond, and R2 and R3 are linked together to form a benzene ring. Then, general formula (Ie) becomes general formula (Ij).

[0053]

[0054] In a preferred embodiment of the present invention

[0055] When Z is NH, Q1 and Q2 are C, respectively.

[0056] Then the general formula (Ⅰe) takes the form of the following general formula (Ⅰk).

[0057]

[0058] In a preferred embodiment of the present invention

[0059] When R1 and R3 are linked together to form NR 11 hour,

[0060] Then general formula (Ⅰb) takes the form of general formula (Ⅰl).

[0061]

[0062] In a preferred embodiment of the present invention

[0063] When R1 and R3 are linked together to form -C(O)NR 11 -hour,

[0064] Then general formula (Ⅰb) takes the form of general formula (Ⅰm).

[0065]

[0066] In a preferred embodiment of the present invention

[0067] When R1 and R3 are linked together to form -NR 11 -hour,

[0068] Then the general formula (Ⅰg) takes the form of the following general formula (Ⅰn).

[0069]

[0070] In a preferred embodiment of the present invention

[0071] When R1 and R3 are linked together to form -C(O)NR 11 -hour,

[0072] Then the general formula (Ⅰg) takes the form of the following general formula (Ⅰo).

[0073]

[0074] In a preferred embodiment of the present invention

[0075] When R1 and R3 are linked together to form -NR 11 -hour,

[0076] Then the general formula (Ⅰi) takes the form of the following general formula (Ⅰp).

[0077]

[0078] In a preferred embodiment of the present invention

[0079] When R1 and R3 are linked together to form -C(O)NR 11 -hour,

[0080] Then the general formula (Ⅰi) takes the form of the following general formula (Ⅰq).

[0081]

[0082] In a preferred embodiment of the present invention

[0083] When R1 and R3 are linked together to form -NR 11 -hour,

[0084] Then the general formula (Ⅰk) takes the form of the following general formula (Ⅰr).

[0085]

[0086] In a preferred embodiment of the present invention

[0087] When R1 and R3 are linked together to form -C(O)NR 11 -hour,

[0088] Then the general formula (Ⅰk) takes the form of the following general formula (Ⅰs).

[0089]

[0090] In a preferred embodiment of the present invention

[0091] R1 can be H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkoxy, borate C1-C4 alkyl, borate C2-C4 alkenyl, borate C2-C4 alkynyl, borate C3-C8 cycloalkyl, halogenated C1-C4 alkyl, halogenated C2-C4 alkenyl, halogenated C2-C4 alkynyl, halogenated C3-C8 cycloalkyl, hydroxyl C1-C4 alkyl, hydroxyl C2-C4 alkenyl, hydroxyl C2-C4 Alkynyl, hydroxyl C3-C8 cycloalkyl, C1-C4 alkylamine, C2-C4 enamine, C2-C4 alkynamine, C3-C8 cycloalkylamine, C1-C4 amino C1-C4 alkyl, C1-C4 amino C2-C4 alkenyl, C1-C4 amino C2-C4 alkynyl, C1-C4 amino C3-C8 cycloalkyl, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkoxy C2-C4 alkenyl, C1-C4 alkoxy C2-C4 alkynyl, C1-C4 alkoxy C3-C8 cycloalkyl, C1-C4 aldehyde, C1-C4 carbonyl, C1-C4 carboxyl, R11 ON=CR 11 -、R 11 C(O)NR 11 - Unsubstituted or substituted with 1 to 2 R” C6 to C10 aryl groups; unsubstituted or substituted with 1 to 2 R” C2 to C6 heteroaryl groups containing 1 to 2 heteroatoms selected from N, O or S; or unsubstituted or substituted with 1 to 2 R” C2 to C6 heterocyclic groups containing 1 to 2 heteroatoms selected from N, O or S.

[0092] In a preferred embodiment of the present invention

[0093] R1 represents H, halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C6 cycloalkoxy, borate C1-C3 alkyl, borate C2-C3 alkenyl, borate C2-C3 alkynyl, borate C3-C6 cycloalkyl, halogenated C1-C3 alkyl, halogenated C2-C3 alkenyl, halogenated C2-C3 alkynyl, halogenated C3-C6 cycloalkyl, hydroxyl C1-C3 alkyl, hydroxyl C2-C3 alkenyl, hydroxyl C2-C3 Alkyne, hydroxy C3-C6 cycloalkyl, C1-C3 alkylamine, C2-C3 enamine, C2-C3 alkynamine, C3-C6 cycloalkylamine, C1-C3 amino C1-C3 alkyl, C1-C3 amino C2-C3 alkenyl, C1-C3 amino C2-C3 alkynyl, C1-C3 amino C3-C6 cycloalkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkoxy C2-C3 alkenyl, C1-C3 alkoxy C2-C3 alkynyl, C1-C3 alkoxy C3-C6 cycloalkyl, C1-C3 aldehyde, C1-C3 carbonyl, C1-C3 carboxyl, R 11 ON=CR 11 -、R 11 C(O)NR 11 - C6 aryl groups that are unsubstituted or substituted with 1 to 2 R”; C2 to C5 heteroaryl groups that are unsubstituted or substituted with 1 to 2 R” and contain 1 to 2 heteroatoms selected from N, O or S; or C2 to C5 heterocyclic groups that are unsubstituted or substituted with 1 to 2 R” and contain 1 to 2 heteroatoms selected from N, O or S.

[0094] In a preferred embodiment of the present invention

[0095] Each R2 is independently H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C3-C8 cycloalkoxy, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C2-C4 alkynyl, halo-C3-C8 cycloalkyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, hydroxy-C2-C4 alkynyl, hydroxy-C3-C8 cycloalkyl, C1-C4 alkylamine C1-C4 amino, C2-C4 alkyne, C3-C8 cycloalkylamine, C1-C4 amino-C1-C4 alkyl, C1-C4 amino-C2-C4 alkenyl, C1-C4 amino-C2-C4 alkyne, C1-C4 amino-C3-C8 cycloalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy-C2-C4 alkenyl, C1-C4 alkoxy-C2-C4 alkyne, C1-C4 alkoxy-C3-C8 cycloalkyl, C1-C4 aldehyde, C1-C4 carbonyl, or C1-C4 carboxyl.

[0096] In a preferred embodiment of the present invention

[0097] Each R2 is independently H, halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C6 cycloalkoxy, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C2-C3 alkynyl, halo-C3-C6 cycloalkyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, hydroxy-C2-C3 alkynyl, hydroxy-C3-C6 cycloalkyl, C1-C3 alkylamine C1-C3 amino, C2-C3 alkynamine, C3-C6 cycloalkylamine, C1-C3 amino-C1-C3 alkyl, C1-C3 amino-C2-C3 alkenyl, C1-C3 amino-C2-C3 alkynyl, C1-C3 amino-C3-C6 cycloalkyl, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C2-C3 alkenyl, C1-C3 alkoxy-C2-C3 alkynyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 aldehyde, C1-C3 carbonyl, or C1-C3 carboxyl.

[0098] In a preferred embodiment of the present invention

[0099] R3 can be H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C3-C8 cycloalkoxy, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C2-C4 alkynyl, halo-C3-C8 cycloalkyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, hydroxy-C2-C4 alkynyl, hydroxy-C3-C8 cycloalkyl, or C1-C4 alkylamine. C2-C4 enamine, C2-C4 alkynamine, C3-C8 cycloalkylamine, C1-C4 amino-C1-C4 alkyl, C1-C4 amino-C2-C4 alkenyl, C1-C4 amino-C2-C4 alkynyl, C1-C4 amino-C3-C8 cycloalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy-C2-C4 alkenyl, C1-C4 alkoxy-C2-C4 alkynyl, C1-C4 alkoxy-C3-C8 cycloalkyl, C1-C4 aldehyde, C1-C4 carbonyl, or C1-C4 carboxyl.

[0100] In a preferred embodiment of the present invention

[0101] R3 can be H, halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C6 cycloalkoxy, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C2-C3 alkynyl, halo-C3-C6 cycloalkyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, hydroxy-C2-C3 alkynyl, hydroxy-C3-C6 cycloalkyl, or C1-C3 alkylamine. C2-C3 enamine, C2-C3 alkynamine, C3-C6 cycloalkylamine, C1-C3 amino-C1-C3 alkyl, C1-C3 amino-C2-C3 alkenyl, C1-C3 amino-C2-C3 alkynyl, C1-C3 amino-C3-C6 cycloalkyl, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C2-C3 alkenyl, C1-C3 alkoxy-C2-C3 alkynyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 aldehyde, C1-C3 carbonyl, or C1-C3 carboxyl.

[0102] In a preferred embodiment of the present invention

[0103] R4 can be H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C3-C8 cycloalkoxy, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C2-C4 alkynyl, halo-C3-C8 cycloalkyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, hydroxy-C2-C4 alkynyl, hydroxy-C3-C8 cycloalkyl, or C1-C4 alkylamine. C2-C4 enamine, C2-C4 alkynamine, C3-C8 cycloalkylamine, C1-C4 amino-C1-C4 alkyl, C1-C4 amino-C2-C4 alkenyl, C1-C4 amino-C2-C4 alkynyl, C1-C4 amino-C3-C8 cycloalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy-C2-C4 alkenyl, C1-C4 alkoxy-C2-C4 alkynyl, C1-C4 alkoxy-C3-C8 cycloalkyl, C1-C4 aldehyde, C1-C4 carbonyl, or C1-C4 carboxyl;

[0104] Alternatively, R4 and R5 can be linked together to form unsubstituted or substituted C1-C4 alkane chains or C2-C4 alkene chains.

[0105] In a preferred embodiment of the present invention

[0106] R4 can be H, halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C6 cycloalkoxy, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C2-C3 alkynyl, halo-C3-C6 cycloalkyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, hydroxy-C2-C3 alkynyl, hydroxy-C3-C6 cycloalkyl, or C1-C3 alkylamine. C2-C3 enamine, C2-C3 alkynamine, C3-C6 cycloalkylamine, C1-C3 amino C1-C3 alkyl, C1-C3 amino C2-C3 alkenyl, C1-C3 amino C2-C3 alkynyl, C1-C3 amino C3-C6 cycloalkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C3 alkoxy C2-C3 alkenyl, C1-C3 alkoxy C2-C3 alkynyl, C1-C3 alkoxy C3-C6 cycloalkyl, C1-C3 aldehyde, C1-C3 carbonyl or C1-C3 carboxyl;

[0107] Alternatively, R4 and R5 can be linked together to form unsubstituted or substituted C2-C3 alkane or C2-C3 alkene chains.

[0108] In a preferred embodiment of the present invention

[0109] R5 can be H, halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C3-C8 cycloalkoxy, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C2-C4 alkynyl, halo-C3-C8 cycloalkyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, hydroxy-C2-C4 alkynyl, hydroxy-C3-C8 cycloalkyl, or C1-C4 alkylamine. C2-C4 enamine, C2-C4 alkynamine, C3-C8 cycloalkylamine, C1-C4 amino-C1-C4 alkyl, C1-C4 amino-C2-C4 alkenyl, C1-C4 amino-C2-C4 alkynyl, C1-C4 amino-C3-C8 cycloalkyl, C1-C4 alkoxy-C1-C4 alkyl, C1-C4 alkoxy-C2-C4 alkenyl, C1-C4 alkoxy-C2-C4 alkynyl, C1-C4 alkoxy-C3-C8 cycloalkyl, C1-C4 aldehyde, C1-C4 carbonyl, or C1-C4 carboxyl.

[0110] In a preferred embodiment of the present invention

[0111] R5 can be H, halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyloxy, C2-C3 alkynyloxy, C3-C6 cycloalkoxy, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C2-C3 alkynyl, halo-C3-C6 cycloalkyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, hydroxy-C2-C3 alkynyl, hydroxy-C3-C6 cycloalkyl, or C1-C3 alkylamine. C2-C3 enamine, C2-C3 alkynamine, C3-C6 cycloalkylamine, C1-C3 amino-C1-C3 alkyl, C1-C3 amino-C2-C3 alkenyl, C1-C3 amino-C2-C3 alkynyl, C1-C3 amino-C3-C6 cycloalkyl, C1-C3 alkoxy-C1-C3 alkyl, C1-C3 alkoxy-C2-C3 alkenyl, C1-C3 alkoxy-C2-C3 alkynyl, C1-C3 alkoxy-C3-C6 cycloalkyl, C1-C3 aldehyde, C1-C3 carbonyl, or C1-C3 carboxyl.

[0112] In a preferred embodiment of the present invention, R4 and R5 are linked together to form an unsubstituted or substituted C1-C4 alkane chain or a C2-C4 alkene chain.

[0113] In a preferred embodiment of the present invention, R4 and R5 are linked together to form an unsubstituted or substituted C2-C3 alkane chain or a C2-C3 alkene chain.

[0114] In a preferred embodiment of the present invention

[0115] R N1 R Y1 R Y2 Independently, it can be H, halogen, CN, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkenyl, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C1-C4 alkoxy, halo-C1-C4 alkenyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, C1-C4 alkoxy-C1-C4 alkyl, NH2-C1-C4 alkylene, (C1-C4 alkyl)NH(C1-C4 alkylene)-, (C1-C4 alkyl)2N(C1-C4 alkylene)- or (R N2 )2N-;R N2 Independently, it is H, halogen, CN, OH, C1-C4 alkyl, C2-C4 alkenyl, halo-C1-C4 alkyl, hydroxy-C1-C4 alkyl, C1-C4 alkoxy, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked by 1 to 6 R's;

[0116] Or R N1 and R Y1 They covalently form C1-C3 alkyl chains or C2-C3 olefin chains with 1-2 R's.

[0117] In a preferred embodiment of the present invention

[0118] R N1 R Y1 R Y2 Independently, it is H, halogen, CN, OH, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 alkenyl, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C1-C3 alkoxy, halo-C1-C3 alkenyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, C1-C3 alkoxy-C1-C3 alkyl, NH2C1-C3 alkylene, (C1-C3 alkyl)NH(C1-C3 alkylene)-, (C1-C3 alkyl)2N(C1-C3 alkylene)- or (R N2 )2N-;R N2 Independently, it is H, halogen, CN, OH, C1-C3 alkyl, C2-C3 alkenyl, halo-C1-C3 alkyl, hydroxy-C1-C3 alkyl, C1-C3 alkoxy, or (R N2 )2N- is a 6-membered heteroalkyl ring group with 2 to 5 R' atoms linked together;

[0119] Or R N1 and R Y1 They covalently form C1-C2 alkane chains or C2-C3 alkene chains with 1-2 R's.

[0120] In a preferred embodiment of the present invention

[0121] Each R' is independently H, halogen, CN, OH, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkenyl, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C1-C4 alkoxy, halo-C1-C4 alkenyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, C1-C4 alkoxy-C1-C4 alkyl, NH2C1-C4 alkylene, (C1-C4 alkyl)NH(C1-C4 alkylene)-, (C1-C4 alkyl)2N(C1-C4 alkylene)-, or (C1-C4 alkyl)2N-;

[0122] Alternatively, two R's on the same ring can covalently form an unsubstituted or substituted C1-C3 alkane or C2-C3 alkene chain;

[0123] R 11 Independently, it can be H, C1-C4 alkyl, C1-C4 alkenyl, hydroxy C1-C4 alkyl, or C1-C4 alkoxy C1-C4 alkyl;

[0124] R” can be independently a halogen, CN, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C4 alkenyl, halo-C1-C4 alkyl, halo-C2-C4 alkenyl, halo-C1-C4 alkoxy, halo-C1-C4 alkenyl, hydroxy-C1-C4 alkyl, hydroxy-C2-C4 alkenyl, C1-C4 alkoxy-C1-C4 alkyl, NH2-C1-C4 alkylene, (C1-C4 alkyl)NH-, (C1-C4 alkyl)2N- or, (C1-C4 alkyl)NH(C1-C4 alkylene)-, or (C1-C4 alkyl)2N(C1-C4 alkylene)-.

[0125] In a preferred embodiment of the present invention

[0126] Each R' is independently H, halogen, CN, OH, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 alkenyl, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C1-C3 alkoxy, halo-C1-C3 alkenyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, C1-C3 alkoxy-C1-C3 alkyl, NH2C1-C3 alkylene, (C1-C3 alkyl)NH(C1-C3 alkylene)-, (C1-C3 alkyl)2N(C1-C3 alkylene)-, or (C1-C3 alkyl)2N-;

[0127] Alternatively, two R's on the same ring can covalently form an unsubstituted or substituted C1-C3 alkane chain or a C2-C3 alkene chain;

[0128] R 11 Independently, it can be H, C1-C3 alkyl, C1-C3 alkenyl, hydroxy C1-C3 alkyl, or C1-C3 alkoxy C1-C3 alkyl;

[0129] R” can be independently a halogen, CN, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, C1-C3 alkoxy, C1-C3 alkenyl, halo-C1-C3 alkyl, halo-C2-C3 alkenyl, halo-C1-C3 alkoxy, halo-C1-C3 alkenyl, hydroxy-C1-C3 alkyl, hydroxy-C2-C3 alkenyl, C1-C3 alkoxy-C1-C3 alkyl, NH2-C1-C3 alkylene, (C1-C3 alkyl)NH-, (C1-C3 alkyl)2N- or, (C1-C3 alkyl)NH(C1-C3 alkylene)-, or (C1-C3 alkyl)2N(C1-C3 alkylene)-.

[0130] In a preferred embodiment of the present invention, the compound is:

[0131]

[0132]

[0133] Another object of the present invention is to provide the use of the compounds of general formula (I) described herein in the treatment of lung cancer. Specifically, this use is in the preparation of drugs for treating lung cancer, particularly in the treatment of non-small cell lung cancer.

[0134] Another object of the present invention is to provide a pharmaceutical composition comprising a compound of general formula (I) as described herein or a pharmaceutically acceptable salt or pharmaceutically acceptable excipient thereof.

[0135] Another object of the present invention is to provide the use of compounds of general formula (I) in inhibiting EGFR.

[0136] The synthesis process of the compound of general formula (I) of the present invention is as follows:

[0137]

[0138] The positive and progressive effects of this invention are as follows: the compounds of general formula (I) of this invention have good inhibitory activity against the C797S drug resistance mutation in the EGFR gene. Detailed Implementation

[0139] Example 1: Synthesis of intermediates A1 and A2

[0140]

[0141] Compound A1-2:

[0142]

[0143] Thioglycolic acid (7.17 g, 78.01 mmol) was added to a mixture of compound A1-1 (10.0 g, 70.92 mmol) and potassium carbonate (29.3 g, 212.76 mmol) in anhydrous DMF (350 mL), and the reaction mixture was heated to 60 °C and reacted for 2 hours. After the reaction mixture cooled, it was poured into 3.5 L of water, the pH was adjusted to acidic with hydrochloric acid, the precipitated solid was filtered, and dried to obtain a yellow solid, A1-2.

[0144] Compound A1-3:

[0145]

[0146] Compound A1-2 (11.0 g, 51.64 mmol) was dissolved in 1,2-dichloroethane (172 mL) and a catalytic amount of DMF was added. Then, thionyl chloride (4.1 mL, 56.80 mmol) was added dropwise to the mixture. After the addition was complete, the reaction solution was heated to 60 °C and reacted for 2 hours to obtain the acyl chloride.

[0147] 86 mL of 1,2-dichloroethane was poured into a three-necked flask, and 8.24 g (61.97 mmol) of aluminum trichloride was added. The previously prepared acyl chloride reaction solution was transferred to a dropping funnel and then slowly added dropwise to the aluminum trichloride solution in 1,2-dichloroethane at 0 °C, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound A1-3.

[0148] Compound A1-4:

[0149]

[0150] Compound A1-3 (2.5 g, 12.82 mmol) was dissolved in 65 mL of DCM, and triethylamine (5.34 mL, 38.46 mL) and DMAP (312 mg, 2.56 mmol) were added. The reaction mixture was stirred at 0 °C for 30 minutes, and trifluoromethanesulfonic anhydride (5.42 g, 19.22 mmol) was slowly added. The reaction mixture was then slowly heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography to obtain compound A1-4.

[0151] 1H NMR (400MHz, DMSO-d6) δppm 8.60 (d, J = 0.8Hz, 1H), 8.41 (s, 1H), 8.30-8.27 (m, 1H), 7.88 (t, J = 8Hz, 1H).

[0152] Intermediates A1 and A2:

[0153]

[0154] Compound A1-4 (3.5 g, 10.70 mmol) was dissolved in 100 mL of ethanol, and platinum dioxide (450 mg) was added. The reaction mixture was reacted at room temperature under a hydrogen pressure of 1.5 MPa for 48 hours. After the reaction was complete, the reaction mixture was filtered, the filtrate was concentrated, and purified by column chromatography to obtain intermediate A1: LCMS: [M+H] + =152.1, and A2:LCMS:[M+H] + =150.1.

[0155] Example 2 Synthesis of intermediate A3

[0156]

[0157] Compound A3-2:

[0158]

[0159] 3-Mercaptopropionic acid (41.3 g, 390.02 mmol) was added to a mixture of compound A3-1 (50.0 g, 354.56 mmol) and potassium carbonate (147 g, 1063.68 mmol) in anhydrous DMF (1.77 L), and the reaction mixture was heated to 60 °C and reacted for 2 hours. After the reaction mixture cooled, it was poured into 20 L of water, the pH was adjusted to acidic with hydrochloric acid, the precipitated solid was filtered, dried, and recrystallized from ethanol to give a yellow solid A3-2.

[0160] Compound A3-3:

[0161]

[0162] Compound A3-2 (145.46 g, 674.79 mmol) was dissolved in 2.1 L of 1,2-dichloroethane and 0.5 mL of DMF was added. Then, 51.2 mL of thionyl chloride (704.87 mmol) was added dropwise to the mixture. After the addition was complete, the reaction solution was heated to 60 °C and reacted for 2 hours to obtain the acyl chloride.

[0163] 1,2-Dichloroethane (1.1 L) was poured into a three-necked flask, and aluminum trichloride (102.3 g, 768.95 mmol) was added. The previously prepared acyl chloride reaction solution was transferred to a dropping funnel and then slowly added dropwise to the aluminum trichloride solution in 1,2-dichloroethane at 0 °C, and the reaction was allowed to proceed at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound A3-3.

[0164] 1 H NMR (400MHz, CDCl3) δ8.48 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 8.38 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 3.23-3.19 (m, 2H), 3.09-3.05 (m, 2H).

[0165] Compound A3-4:

[0166]

[0167] Compound A3-3 (7.8 g, 37.32 mmol) was dissolved in 600 mL of methanol. Cobalt chloride hexahydrate (17.76 g, 74.64 mmol) was added at 0 °C, followed by sodium borohydride (14.18 g, 373.2 mmol) in portions. The mixture was reacted at 0 °C for 1 h. After the reaction was complete, water was slowly added to quench the reaction mixture. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 6.5 g of a pale yellow solid.

[0168] Intermediate A3:

[0169]

[0170] Compound A3-4 (6.5 g, 35.85 mmol) and triethylsilane (41.5 g, 358.5 mmol) were added to 180 mL of trifluoroacetic acid. The solution was heated at 60 °C for 3 h. After the reaction was complete, the reaction solution was concentrated. Dichloromethane was added to the concentrated solution, and the precipitated solid was filtered to obtain 6.6 g of white solid.

[0171] Example 3 Synthesis of Intermediate A4

[0172]

[0173] Compound A4-2:

[0174]

[0175] Compound A4-1 (10.0 g, 62.89 mmol) and potassium carbonate (21.7 g, 57.2 mmol) were mixed in DMF (300 mL), and 3-mercaptopropionic acid (7.35 g, 69.28 mmol) was added dropwise at 0 °C. After the addition was complete, the reaction solution was allowed to rise naturally from 0 °C to room temperature and stirred for 2 hours. Once the reaction was complete, the reaction solution was poured into water, and the pH was adjusted to 3 with 4 mol / L HCl. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and slurried with ethanol to give a yellow solid compound A4-2 (6.28 g, yield 41%). MS m / z (ESI): 244.1 [MH] - .

[0176] Compound A4-3:

[0177]

[0178] Compound A4-2 (2.0 g, 8.16 mmol) and DMF (3 drops) were dissolved in dichloroethane (30 mL), and sulfoxide (0.65 mL, 8.98 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, it was cooled to room temperature, and the mixture was added dropwise to dichloroethane (15 mL) containing aluminum trichloride (1.31 g, 9.79 mmol) at 0 °C. The reaction mixture was heated to 45 °C and stirred for 2 hours. After the reaction was complete, it was cooled to room temperature and quenched slowly in ice water. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a pale yellow solid compound A4-3 (260 mg, yield 14%).

[0179] 1 H NMR (400MHz, CDCl3) δ8.39-8.35(m,1H),7.03(t,J=10.0Hz,1H),3.23-3.19(m,2H),3.08-3.05(m,2H).

[0180] Compound A4-4:

[0181]

[0182] Compound A4-3 (260 mg, 1.14 mmol) and triethylsilane (664 mg, 5.73 mmol) were dissolved in trifluoroacetic acid (4 mL) and stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain crude product 048-4 (180 mg), which was used directly in the next step.

[0183] Intermediate A4:

[0184]

[0185] Zinc powder was added to a 14 mL solution of acetic acid containing 180 mg (0.84 mmol) of A4-4 and stirred for 10 minutes at room temperature. The reaction mixture was filtered, the filtrate was concentrated, neutralized with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give a yellow oily intermediate A4 (95 mg, 62% yield). MS m / z (ESI): 183.9 (M+H) + .

[0186] Example 4 Synthesis of intermediate A5

[0187]

[0188] Compound A5-1:

[0189]

[0190] Intermediate A3 (20.0 g, 71.68 mmol) was dissolved in water (300 mL), and the pH was adjusted to 8-9 with NaHCO3. The mixture was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered and concentrated to give a gray solid, compound A5-1 (12.0 g, 100% yield). MS m / z (ESI): 166 (M+H) + .

[0191] Intermediate A5:

[0192]

[0193] At 0 °C, a solution of acetic anhydride (11.7 g, 115.15 mmol) in acetic acid (30 mL) was added dropwise to a solution of compound A5-1 (9.5 g, 57.58 mmol) in acetic acid (100 mL). The reaction mixture was stirred at room temperature for 4 h. After the reaction was complete, the solvent was removed under reduced pressure to give a gray solid A5 (11.3 g, 95% yield). MS m / z (ESI): 208 (M+H) + .

[0194] Example 5: Synthesis of Intermediate A6

[0195]

[0196] Intermediate A6:

[0197]

[0198] Intermediate A3 (2.0 g, 12 mmol) was dissolved in 30 mL of N,N-dimethylformamide. N-bromosuccinimide (2.37 g, 13.2 mmol) was slowly added under ice-water bath conditions, and the reaction was carried out under ice-water bath conditions for 1 hour. After the reaction was completed, water was added, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, dried, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 2.2 g of a pale purple solid.

[0199] Example 6 Synthesis of Intermediate A7

[0200]

[0201] Compound A7-1:

[0202]

[0203] Intermediate A5 (5.5 g, 26.57 mmol) was dissolved in trifluoroacetic acid (100 mL), and N-chlorosuccinimide (6.4 g, 47.82 mmol) was added in portions at room temperature. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid compound A7-1 (3.6 g, 56% yield). MS m / z (ESI): 242 (M+H) + .

[0204] Intermediate A7:

[0205]

[0206] Compound A7-1 (3.6 g, 14.87 mmol) was dissolved in concentrated hydrochloric acid (40 mL) and stirred at 110 °C for 3 h. After the reaction was complete, the reaction solution was cooled to 0 °C, the pH was adjusted to 9-10 with sodium hydroxide, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a pale yellow solid intermediate A7 (2.9 g, 98% yield). MS m / z (ESI): 200 (M+H) + .

[0207] Example 7 Synthesis of Intermediate B1

[0208]

[0209] Compound B1-2:

[0210]

[0211] 20 g of 3-fluoro-4-methylphenol (158.59 mmol) was dissolved in 200 mL of DCM. At room temperature, 15.71 mL of 70% concentrated nitric acid (174.33 mmol) solution was slowly added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and extracted to obtain the crude product. The crude product was purified by column chromatography to give 17.8 g of a yellow solid.

[0212] 1 HNMRδ (CDCl3, 400MHz), 7.99 (dd, J = 10Hz, 0.8Hz, 1H), 6.80 (d, J = 10Hz, 1H), 2.60 (3H, s).

[0213] Compound B1-3:

[0214]

[0215] Compound B1-2 (17.8 g, 104.01 mmol) was dissolved in 100 mL of DMF, and then potassium carbonate (21.5 g, 156.02 mmol) was added. Iodomethane (7.78 mL, 124.81 mmol) was slowly added dropwise to the reaction mixture at room temperature, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, extracted to obtain the crude product, and purified by column chromatography to give 16.8 g of a yellow solid.

[0216] 1 H NMR (400MHz, DMSO-d6) δppm 7.92 (d, J = 8.1Hz, 1H), 7.25 (d, J = 11.7Hz, 1H), 3.89 (s, 3H), 2.19 (d, J = 1.5Hz, 3H).

[0217] Compound B1-4:

[0218]

[0219] Compound B1-3 (10 g, 54.01 mmol) was dissolved in 54 mL of DMF. Potassium carbonate (11.18 g, 81.01 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (9.9 g, 54.01 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at 60 °C for 15 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to give 10.2 g of a yellow solid.

[0220] 1H NMR (400MHz, CDCl3) δppm 7.85-7.77(m,1H),6.54(s,1H),3.94(s,3H),3.35(d,2H),2.78-2.63(m,5H ),2.60-2.48(m,4H),2.32(s,3H),2.24(s,3H),1.99(d,2H),1.72(dd,2H).

[0221] Intermediate B1:

[0222]

[0223] Compound B1-4 (5.0 g, 14.35 mmol) was dissolved in 30 mL of methanol, and 500 mg of 10% wet palladium on carbon was added at room temperature. The reaction system was purged with hydrogen three times and stirred overnight at room temperature under normal pressure. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain intermediate B1, which was directly used in the next reaction.

[0224] 1 H NMR (400MHz, CDCl3) δppm 6.55(d,J=2.8Hz,2H),3.84(s,3H),3.10(d,J=11.6Hz,2H),2.71-2.56(m,1 1H),2.41-2.35(m,5H),2.19(s,3H),1.75-1.73(m,2H),1.73-1.68(m,2H).

[0225] Example 8 Synthesis of Intermediate B2

[0226]

[0227] Compound B2-2:

[0228]

[0229] Compound B2-1 (10.0 g, 49.1 mmol) was dissolved in 40 mL of concentrated sulfuric acid. Potassium nitrate (4.95 g, 49.1 mmol) was added in portions at 0 °C, and the reaction mixture was reacted at 0 °C for 1 hour. After the reaction was complete, the mixture was cooled and poured into ice water. It was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 11.0 g of a yellow solid.

[0230] Compound B2-3:

[0231]

[0232] B2-2 (6.04 g, 24.25 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (4.66 g, 25.46 mmol), and potassium carbonate (6.7 g, 48.5 mmol) were added to 120 mL of DMF and reacted overnight at 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and 150 mL of water was added to the filtrate. The solution was extracted three times with ethyl acetate and purified by column chromatography (dichloromethane / methanol / ammonia = 50:1:3%) to give 5.9 g of a yellow solid.

[0233] Compound B2-4:

[0234]

[0235] Under nitrogen protection, compound 004-3 (5.9 g, 14.3 mmol), allyl tributyltin (5.69 g, 17.2 mmol), and tetrakis(triphenylphosphine) palladium (1.65 g, 1.43 mmol) were added to 70 mL of 1,4-dioxane. The solution was reacted overnight at 100 °C. After the reaction was complete, the reaction solution was concentrated and purified by column chromatography (dichloromethane / methanol / ammonia = 50:1:3%) to give 5.0 g of yellow solid.

[0236] Compound B2:

[0237]

[0238] Under nitrogen protection, compound 004-4 (5.0 g, 13.37 mmol), iron powder (4.5 g, 80.2 mmol), and ammonium chloride (7.1 g, 133.7 mmol) were added to 50 mL of ethanol and 15 mL of water, and heated at 60 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography (dichloromethane / methanol = 1%) to give 4.5 g of gray solid.

[0239] Example 9 Synthesis of Intermediate B3

[0240]

[0241] Intermediate B3:

[0242]

[0243] Intermediate B2 (400 mg, 1.16 mmol) was dissolved in 10 mL of tetrahydrofuran, and borane (2 M tetrahydrofuran solution, 23.26 mmol) was added dropwise at 0 °C. The reaction was carried out at room temperature for 3 hours. After the reaction was complete, dilute hydrochloric acid (2 M) was added to the solution and stirred overnight. The pH of the solution was then adjusted to 8–9 with potassium carbonate. The solution was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solution was dried, filtered, concentrated, and purified by thin-layer chromatography (dichloromethane / methanol = 10:1) to give 1.0 g of brown solid.

[0244] Example 10 Synthesis of Intermediate B4

[0245]

[0246] Compound B4-2:

[0247]

[0248] Under a nitrogen atmosphere, compound B4-1 (10.0 g, 70.9 mmol) was added to 55 mL of concentrated sulfuric acid. Potassium nitrate (7.2 g, 70.9 mmol) was slowly added in an ice bath, and the reaction mixture was allowed to react for 2 hours in an ice bath. After the reaction was complete, the reaction mixture was poured into ice water, the pH was adjusted to neutral with sodium hydroxide, and the solution was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 9.7 g of a yellow solid.

[0249] Compound B4-3:

[0250]

[0251] Compound B4-2 (4.0 g, 21.5 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (4.3 g, 23.6 mmol), and potassium carbonate (5.9 g, 43 mmol) were added to 70 mL of DMF and reacted overnight at 80 °C. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and the crude product was purified by alkaline silica gel column chromatography to obtain 5.2 g of yellow solid.

[0252] Compound B4-4:

[0253]

[0254] Compound B4-3 (5.2 g, 14.9 mmol), allyl chloroformate (7.2 g, 60 mmol), and triethylamine (4.5 g, 45 mmol) were dissolved in 60 mL of dichloromethane and reacted overnight at room temperature. After direct concentration, the crude product was purified by alkaline silica gel column chromatography to obtain 3.3 g of a pale yellow solid.

[0255] Intermediate B4:

[0256]

[0257] Compound B4-4 (3.3 g, 7.6 mmol), ammonium chloride (4.0 g, 76 mmol), and iron powder (2.5 g, 45.6 mmol) were added to 30 ml of ethanol and 5 ml of water. The mixture was heated at 60 °C for 2 hours. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and the crude product was purified by alkaline silica gel column chromatography to obtain 3.0 g of reddish-black solid.

[0258] Example 11 Synthesis of Intermediate B5

[0259]

[0260] Compound B5-2:

[0261]

[0262] Compound B5-1 (1 g, 5.4 mmol) and 4-dimethylaminopiperidine (1.04 g, 8.1 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and potassium carbonate (2.2 g, 16.2 mmol) was added. The reaction mixture was reacted overnight at 65 °C under nitrogen protection. After the reaction mixture was cooled to room temperature, it was added to 100 mL of water, extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane / methanol = 1 / 20) to give 850 mg of a yellow solid, yield: 53%, LCMS: [M+H] + =294.2.

[0263] Intermediate B5:

[0264]

[0265] Compound B5-2 (400 mg, 1.52 mmol) was dissolved in 20 mL of methanol, and 40 mg of 10% wetted palladium on carbon was added. The reaction was carried out under normal pressure for 3 hours. After the reaction was completed, the reaction solution was filtered directly, and the filtrate was concentrated to give 360 ​​mg of a dark purple solid product. Yield: 90%. LCMS: [M+H] + =264.2.

[0266] Example 12 Synthesis of Intermediate B6

[0267]

[0268] Compound B6-2:

[0269]

[0270] Compound B6-1 (10.0 g, 48.78 mmol) was dissolved in 50 mL of concentrated sulfuric acid. Potassium nitrate (4.93 g, 48.78 mmol) was added in portions at 0 °C, and the reaction mixture was reacted at 0 °C for 30 minutes. After the reaction was complete, the mixture was cooled and poured into ice water. It was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid (8.3 g, yield: 68%).

[0271] Compound B6-3:

[0272]

[0273] Compound B6-2 (5.0 g, 20 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (3.85 g, 21 mmol), and potassium carbonate (5.52 g, 40 mmol) were added to 100 mL of DMF and reacted at 80 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with methyl tert-butyl ether to give a yellow solid compound B6-3 (4.78 g, yield: 58%). MS m / z (ESI): 415.1 [M+H] +

[0274] Compound B6-4:

[0275]

[0276] Compound B6-3 (3 g, 7.26 mmol), tributylvinyltin (4.6 g, 14.52 mmol), bis(triphenylphosphine)palladium dichloride (509 mg, 0.726 mmol), cuprous bromide (312 mg, 2.178 mmol), and triphenylphosphine (570 mg, 2.178 mmol) were stirred overnight at 110 °C under nitrogen protection in toluene. After cooling to room temperature, the mixture was concentrated and diluted with dichloromethane. Excess tin reagent was quenched with potassium fluoride, filtered, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was slurried with methyl tert-butyl ether to give yellow compound B6-4 (1.6 g, 61% yield). MS m / z (ESI): 361.2 [M+H] +

[0277] Intermediate B6:

[0278]

[0279] Compound B6-4 (1.6 g, 4.44 mmol) was dissolved in methanol (100 mL), and then 10% wet palladium on carbon (500 mg) was added. The reaction mixture was stirred overnight under atmospheric pressure and hydrogen atmosphere. The reaction mixture was filtered and concentrated to give a brown oily intermediate B6 (1.45 g, 98% yield). MS m / z (ESI): 333.3 [M+H] + .

[0280] Example 13 Synthesis of Intermediate C1

[0281]

[0282] Compound C1-1:

[0283]

[0284] Intermediate A3 (2.5 g, 9.54 mmol), 2,4,5-trichloropyrimidine (3.49 g, 19.08 mmol), and N,N-diisopropylethylamine (3.69 g, 28.62 mmol) were added to 50 mL of ethanol. The solution was reacted overnight at 90 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and crystals precipitated. The precipitated crystals were filtered to obtain 2.0 g of a pale yellow solid.

[0285] Compound C1:

[0286]

[0287] Compound C1-1 (2.0 g, 6.4 mmol) and sodium perborate tetrahydrate (4.92 g, 32 mmol) were added to 32 ml of acetic acid. The solution was heated at 60 °C for 2 hours. After the reaction was complete, the solution was concentrated, and an appropriate amount of water was added to the reaction solution. The solution was extracted three times with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and sodium brine solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 1.7 g of a pale yellow solid.

[0288] Example 14 Synthesis of intermediate C2

[0289]

[0290] Compound C2-1:

[0291]

[0292] Intermediate A1 (270 mg, 1.79 mmol) was dissolved in 9 mL of ethanol, and 2,4,5-trichloropyrimidine (656 mg, 3.58 mmol) and N,N-diisopropylethylamine (1.18 mL, 7.16 mmol) were added. The reaction mixture was refluxed and stirred overnight. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography to obtain compound C2-1.

[0293] 1 H NMR (400MHz, DMSO-d6): δppm 9.60(s,1H),8.36(s,1H),7.23-7.21(m,1H),7.11-7.10(m,2H),3.33(s,4H).

[0294] Intermediate C2:

[0295]

[0296] Compound C2-1 (318 mg, 1.07 mmol) was dissolved in 1.5 mL of acetic acid, and sodium perborate (820 mg, 5.35 mmol) was added. The reaction mixture was stirred at 60 °C for one hour. After the reaction was complete, the mixture was concentrated and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and brine, dried, filtered, and concentrated. The crude product was then subjected to column chromatography to obtain intermediate C2.

[0297] Example 15 Synthesis of intermediate C3

[0298]

[0299] Compound C3-1:

[0300]

[0301] Intermediate A3 (500 mg, 3.0 mmol) and 5-bromo-2,4-dichloropyrimidine (451 mg, 3.0 mmol) were dissolved in 10 mL of ethanol, and N,N-diisopropylethylamine (928 mg, 7.2 mmol) was added. The reaction solution was refluxed at 90 °C overnight. After the reaction solution was cooled to room temperature, it was concentrated and purified by column chromatography (dichloromethane / methanol = 2:100) to give 530 mg of a yellow solid.

[0302] Intermediate C3:

[0303]

[0304] Under nitrogen protection, compound C3-1 (520 mg, 1.46 mmol) was dissolved in 5 mL of acetic acid, and sodium perborate tetrahydrate (1.1 g, 7.3 mmol) was added at room temperature. The reaction was carried out at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched by adding sodium bisulfite aqueous solution. The solution was concentrated and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (dichloromethane / methanol = 100:1) to give 570 mg of brown solid.

[0305] Example 16 Synthesis of Intermediate C4

[0306]

[0307] Compound C4-1:

[0308]

[0309] Intermediate A4 (95 mg, 0.52 mmol), 5-bromo-2,4-dichloropyrimidine (118 mg, 0.52 mmol), and DIEA (201 g, 1.56 mmol) were dissolved in ethanol (4 mL) and stirred at 80 °C for 16 hours. After cooling to room temperature, the solution was concentrated and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give a yellow solid compound C4-1 (100 mg, 51% yield). MS m / z (ESI): 376.0 (M+H) + .

[0310] Intermediate C4:

[0311]

[0312] Compound C4-1 (100 mg, 0.267 mmol) and sodium perborate tetrahydrate (142 mg, 1.33 mmol) were added to acetic acid (4 mL) and heated at 60 °C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a light red solid intermediate C4 (110 mg, 100% yield). MS m / z (ESI): 408.0 (M+H) + .

[0313] Example 17 Synthesis of Intermediate C5

[0314]

[0315] Compound C5-1:

[0316]

[0317] Intermediate A6 (150 mg, 0.62 mmol) and 2,4-dichloro-5-bromopyrimidine (704 mg, 3.11 mmol) were dissolved in 5 mL of ethanol, and N,N-diisopropylethylamine (318 mg, 2.41 mmol) was added. The reaction mixture was refluxed at 90 °C overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 210 mg of a yellow solid. MS m / z (ESI): 434.2 [M+H] + .

[0318] Intermediate C5:

[0319]

[0320] Intermediate C5 (200 mg, 0.46 mmol) was dissolved in 10 mL of acetic acid, and sodium perborate (356 mg, 2.31 mmol) was added. The reaction mixture was reacted at 85 °C for 3 hours. After the reaction mixture cooled to room temperature, the reaction was quenched with an aqueous sodium bisulfite solution, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 170 mg of a brownish-yellow solid. MS m / z (ESI): 466.1 [M+H] + .

[0321] Example 18 Synthesis of intermediate C6

[0322]

[0323] Compound C6-1:

[0324]

[0325] Intermediate A4 (130 mg, 0.71 mmol), 2,4,5-trichloropyrimidine (390 mg, 2.13 mmol), and DIEA (275 mg, 2.13 mmol) were dissolved in ethanol (5 mL) and stirred at 80 °C for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethanol to give a white solid compound C6-1 (124 mg, 53% yield). MS m / z (ESI): 330 (M+H) + .

[0326] Intermediate C6:

[0327]

[0328] Compound C6-1 (124 mg, 0.38 mmol) and sodium perborate tetrahydrate (289 mg, 1.88 mmol) were added to acetic acid (5 mL), and the solution was heated at 60 °C for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid intermediate C6 (110 mg, yield 81%). MS m / z (ESI): 362 (M+H) + .

[0329] Example 19 Synthesis of intermediate C7

[0330]

[0331] Compound C7-1:

[0332]

[0333] Intermediate A6 (140 mg, 0.57 mmol) and 2,4,5-trichloropyrimidine (527 mg, 2.91 mmol) were dissolved in 5 mL of ethanol. N,N-diisopropylethylamine (310 mg, 2.41 mmol) was added, and the reaction mixture was refluxed at 90 °C overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 180 mg of a yellow solid. MS m / z (ESI): 390.5 [M+H] + .

[0334] Intermediate C7:

[0335]

[0336] Compound C7-1 (180 mg, 0.47 mmol) was dissolved in 10 mL of acetic acid, and sodium perborate (360 mg, 2.34 mmol) was added. The reaction solution was reacted at 85 °C for 3 hours. After the reaction solution cooled to room temperature, the reaction was quenched with an aqueous sodium bisulfite solution, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 120 mg of a brownish-yellow solid. MS m / z (ESI): 422.3 [M+H] + .

[0337] Example 20 Synthesis of intermediate C8

[0338]

[0339] Compound C8-1:

[0340]

[0341] Intermediate A7 (110 mg, 0.55 mmol), 2,4-dichloro-5-bromopyrimidine (502 mg, 2.20 mmol), and DIEA (213 mg, 1.65 mmol) were dissolved in ethanol (15 mL) and stirred at 80 °C for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethanol to give a white solid compound C8-1 (110 mg, 51% yield). MS m / z (ESI): 390 (M+H) + .

[0342] Intermediate C8:

[0343]

[0344] Compound C8-1 (110 mg, 0.28 mmol) and sodium perborate tetrahydrate (217 mg, 1.41 mmol) were added to acetic acid (5 mL), and the solution was heated at 60 °C for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid intermediate C8 (119 mg, 100% yield). MS m / z (ESI): 424 (M+H) + .

[0345] Example 21 Synthesis of intermediate C9

[0346]

[0347] Compound C9-1:

[0348]

[0349] Intermediate A7 (400 mg, 2.00 mmol), 2,4,5-trichloropyrimidine (1.1 g, 6.00 mmol), and DIEA (774 mg, 6.00 mmol) were dissolved in ethanol (15 mL) and stirred at 80 °C for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethanol to give a white solid compound C9-1 (400 mg, yield 58%). MS m / z (ESI): 348 (M+H) + .

[0350] Intermediate C9:

[0351]

[0352] Compound C9-1 (400 mg, 1.15 mmol) and sodium perborate tetrahydrate (888 mg, 5.76 mmol) were added to acetic acid (10 mL), and the solution was heated at 60 °C for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid intermediate C9 (410 mg, 94% yield). MS m / z (ESI): 380 (M+H) + .

[0353] Example 22 Synthesis of target compound 001

[0354]

[0355] Compound 001-2:

[0356]

[0357] Compound 001-1 (3.0 g, 13.7 mmol), dimethylphosphine oxide (1.26 g, 16.2 mmol), palladium acetate (154 mg, 0.68 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (396 mg, 0.68 mmol), and potassium phosphate (3.2 g, 15.1 mmol) were dissolved in 30 mL of DMF and refluxed overnight at 120 °C under nitrogen protection. After cooling to room temperature, the mixture was concentrated, and a suitable amount of water was added. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed three times with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (dichloromethane:methanol = 50:1) to give 2.2 g of a yellow solid. LCMS: [M+H]+ = 169.8.

[0358] Compound 001-3:

[0359]

[0360] Compound 001-2 (2.2 g, 13.4 mmol) and 2,4,5-trichloropyrimidine (4.9 g, 26.8 mmol) were dissolved in 40 mL of ethanol, and N,N-diisopropylethylamine (6.9 g, 53.7 mmol) was added. The reaction mixture was refluxed at 80 °C overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (dichloromethane:methanol = 50:1) to give 3.8 g of a yellow solid. LCMS: [M+H] + =316.2.

[0361] Compound 001-4:

[0362]

[0363] Compound 001-3 (500 mg, 1.6 mmol) and intermediate B2 (550 mg, 1.6 mmol) were dissolved in 20 mL of tert-butanol, and methanesulfonic acid (614.4 mg, 6.4 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and a suitable amount of water was added to the concentrate. The mixture was extracted three times with dichloromethane, the organic phase was discarded, and the aqueous phase was retained. The pH of the aqueous phase was adjusted to 10–11 by adding saturated sodium carbonate solution, and the mixture was extracted three times with dichloromethane. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol = 20:1) to give 400 mg of a yellow solid. LCMS: [M+H] + =624.3.

[0364] Compound 001

[0365]

[0366] Compound 001-4 (100 mg, 0.16 mmol) was dissolved in 2 mL of tetrahydrofuran, and borane dimethyl sulfide solution (1.2 mL, 2.4 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was allowed to react at room temperature for 2 hours. Afterward, 5 mL of 2M dilute HCl solution was added to the reaction mixture, and the reaction was continued with stirring at room temperature for 12 hours. The mixture was then concentrated and purified by preparative column reversed-phase chromatography to give 6.2 mg of a white solid. LCMS: [M+H] + =670.2.

[0367] 1 H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.14(s,1H),8.11-8.09(m,2H),7.57-7.51( m,1H),7.42-7.30(m,3H),7.11(t,J=5.4Hz,1H),6.77(d,J=10.8Hz,1H),3.75(s,3H ),3.02(d,J=13.6Hz,2H),2.72-2.51(m,8H),2.50-2.28(m,6H),2.24(s,3H),1.88 (d,J=9.6Hz,2H),1.78(d,J=13.6Hz,6H),1.62-1.48(m,4H),0.86(t,J=5.4Hz,1H).

[0368] Example 23 Synthesis of target compound 002

[0369]

[0370] Compound 002:

[0371]

[0372] Intermediate B3 (364 mg, 0.93 mmol) and intermediate C1 (320 mg, 0.93 mmol) were dissolved in 10 mL of n-butanol. Methanesulfonic acid (357 mg, 3.72 mmol) was added to the solution. The reaction mixture was reacted overnight at 100 °C. After the reaction was complete, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane. The combined organic phases were washed three times with saturated brine, dried, filtered, and concentrated. The crude product was purified by reversed-phase column chromatography to obtain 80 mg of a white solid.

[0373] 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.19(s,1H),8.13(s,1H),8.05(d,J=8.0Hz,2H),7.38 (t,J=12Hz,4H),7.09(d,J=8.0Hz,1H),6.74(s,1H),3.75(s,3H),3.65-3.62(m,2H),3.03-2 .97(m,4H),2.65(t,J=12.0Hz,2H),2.57-2.53(m,2H),2.43(t,J=8.0Hz2H),2.39-2.32(m,4 H),2.31-2.24(m,6H),2.16(s,3H),1.84(d,16H),1.63-1.43(m,4H),0.60(t,J=8.0Hz,2H).

[0374] Synthesis of target compound 003 in Implementation 24

[0375]

[0376] Compound 003:

[0377]

[0378] Intermediate C1 (200 mg, 0.58 mmol) and intermediate B1 (185 mg, 0.58 mmol) were dissolved in 3 mL of tert-butanol, and methanesulfonic acid (278 mg, 2.9 mmol) was added with stirring. The reaction mixture was refluxed at 90 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and then a suitable amount of 2 mol / L hydrochloric acid aqueous solution was added. The mixture was extracted with dichloromethane. The aqueous phase was collected, and the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and slurried with methanol to obtain 50 mg of white solid CL005-007. LCMS: [M+H] + =626.5.

[0379] 1 H NMR (400MHz, CDCl3) δ9.15(s,1H),8.33(d,J=8.0Hz,1H),8.12(s,1H),8.00(s,1H),7.45-7.39(m,2H),6.99(d,J=7.6Hz,1H),6.62(s,1H),3.85(s, 3H),3.50-3.45(m,2H),3.17-3.13(m,2H),3.09-3.06(m,2H),2.67-2.35 (m,13H),2.33(s,3H),2.14(s,3H),1.97-1.94(s,2H),1.77-1.70(m,2H).

[0380] Example 25 Synthesis of target compound 004

[0381]

[0382] Compound 004-2:

[0383]

[0384] Under nitrogen protection, 10 g (50 mmol) of 2-bromo-3-hydroxybenzaldehyde was dissolved in 100 mL of DMF, followed by the addition of potassium carbonate (13.8 g, 100 mmol) and methyl iodoform (8.52 g, 60 mmol). The reaction mixture was allowed to react at room temperature for 3 hours. A suitable amount of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, washed three times with saturated brine, dried, and concentrated to obtain a crude product. The crude product was purified by column chromatography to give a white solid compound 004-2 (10.6 g, yield: 99%).

[0385] 1H NMR (400MHz, CDCl3) δ10.44(s,1H),7.53(m,1H),7.40(m,1H),7.14(m,1H),3.96(s,3H).

[0386] Compound 004-3:

[0387]

[0388] Under nitrogen protection, methyl bromide triphenylphosphine (21.22 g, 59.44 mmol) was dissolved in 120 mL of THF. Potassium tert-butoxide (6.66 g, 59.44 mmol) was added in an ice-water bath, and the mixture was stirred for 1 hour. Compound 004-2 (10.6 g, 49.53 mmol) was added dropwise, and the temperature was raised to room temperature. The reaction mixture was allowed to react at room temperature for 20 hours. A suitable amount of water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain a colorless oily compound 004-3 (9.5 g, yield: 90%).

[0389] 1 H NMR (400MHz, CDCl3) δ7.26(m,1H),7.20(m,1H),6.84(m,1H),5.73(m,1H),5.40(m,1H),3.92(s,3H).

[0390] Compound 004-4:

[0391]

[0392] Compound 004-3 (9.5 g, 44.81 mmol) was dissolved in a 0.5 M, 134 mL solution of 9-BBN in THF and reacted at room temperature for 20 hours under nitrogen protection. The reaction mixture was then placed in an ice-water bath, and 22.4 mL of 6 N sodium hydroxide aqueous solution (3.0 equivalents) was added. After stirring for 30 minutes, 14.25 mL of hydrogen peroxide solution was added dropwise, and stirring continued for another 30 minutes. Saturated sodium bisulfite aqueous solution was added dropwise until starch-potassium iodide test paper no longer turned blue. The mixture was extracted three times with ethyl acetate, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain a colorless oily compound 004-4 (8.8 g, yield: 85%).

[0393] 1 H NMR (400MHz, CDCl3) δ7.22 (m, 1H), 6.91 (m, 1H), 6.81 (d, J = 8.4Hz, 1H), 3.89 (m, 5H), 3.07 (m, 2H).

[0394] Compound 004-5:

[0395]

[0396] Under nitrogen protection, triphenylphosphine (15.03 g, 57.39 mmol) was dissolved in 120 mL of dry dichloromethane and stirred at room temperature for 10 minutes. Imidazole (6.50 g, 95.65 mmol) was added, and the mixture was stirred at room temperature for another 10 minutes. Iodine (14.56 g, 57.39 mmol) was then added dropwise, followed by compound 004-4 (8.80 g, 38.26 mmol). The reaction was allowed to proceed for 25 hours. Saturated sodium bisulfite aqueous solution was added dropwise to the reaction mixture until starch-potassium iodide paper no longer turned blue. The mixture was extracted three times with dichloromethane, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 004-5 (10.2 g, yield: 78%).

[0397] 1 H NMR (400MHz, CDCl3) δ7.23 (m, 1H), 6.86 (m, 2H), 3.88 (s, 3H), 3.34 (m, 4H).

[0398] Compound 004-6:

[0399]

[0400] Compound 004-5 (10.20 g, 30 mmol) was dissolved in 30 mL of triethyl phosphate and reacted at 120 °C for 24 hours under nitrogen protection. After the reaction was completed, the reaction solution was concentrated and purified by column chromatography to give compound 004-6 (9.61 g, yield: 91%).

[0401] 1 H NMR (400MHz, CDCl3) δ7.22(m,1H),6.91(m,1H),6.81(m,1H),4,15(m,4H),3.91(s,3H),3.07(m,2H),2.09(m,2H),1.34(m,6H).

[0402] Compound 004-7:

[0403]

[0404] Under nitrogen protection, compound 004-6 (9.6 g, 27.43 mmol) was dissolved in THF, and a 1.3 M, 192 mL solution of tert-butyllithium in THF was slowly added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours. After the reaction was complete, water was carefully and slowly added dropwise to the reaction system in a dry ice bath. The mixture was then brought to room temperature and extracted three times with dichloromethane. The organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 004-7 (1.7 g, yield: 27%).

[0405] 1 H NMR (400MHz, CDCl3): δ7.43(m,1H),6.86(m,1H),6.76(m,1H),4.35-4.18(m,2H),3.91(s,3H),3.07(m,2H),2.15(m,2H),1.33(m,3H).

[0406] Compound 004-8:

[0407]

[0408] Under nitrogen protection, compound 004-7 (1.7 g, 7.52 mmol) was dissolved in thionyl chloride, and the reaction mixture was stirred at 60 °C for 2 hours. After cooling to room temperature, the thionyl chloride was removed, and the crude product was used directly in the next reaction step.

[0409] Compound 004-9:

[0410]

[0411] Under nitrogen protection, compound 004-8 (1.2 g, 5.56 mmol) was dissolved in dry THF, and 3 M magnesium methyl bromide diethyl ether solution (1.85 mL, 5.56 mmol) was slowly added dropwise at -78 °C. The reaction mixture was slowly brought to room temperature and stirred for 2 hours. Then, water was slowly added dropwise to quench the reaction in an ice bath. The resulting mixture was extracted three times with ethyl acetate, and the organic phase was collected, dried, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain compound 004-9 (270 mg, yield: 24%).

[0412] H NMR (400MHz, CDCl3): δ7.45(m,1H),6.89(m,1H),6.76(m,1H),3.91(s,3H),3.38(m,1H),3.12(m,1H),2.25(m,1H),2.19(m,1H),1.88(m,3H).

[0413] Compound 004-10:

[0414]

[0415] Under nitrogen protection, compound 004-9 (5.15 g, 26.27 mmol) was dissolved in dry dichloromethane (206 ml), and boron tribromide (12.8 ml, 131.35 mmol) was slowly added dropwise at 0 °C while stirring was continued at 0 °C for 2 hours. Then, methanol was slowly added dropwise to quench the reaction in an ice bath. The mixture was concentrated, slurried with acetone, filtered, and dried to give white compound 10 (3.05 g, 64% yield).

[0416] 1 H NMR(400MHz,DMSO-d6)δ10.24(brs,1H),7.29(t,J=7.6Hz,1H),6.77-6.71(m,2H) ,3.19-3.08(m,1H),2.17-2.09(m,1H),2.00-1.89(m,1H),1.71(d,J=13.6Hz,3H).

[0417] Compound 004-11:

[0418]

[0419] Under nitrogen protection, compound 004-10 (1.5 g, 8.24 mmol) was suspended in dry dichloromethane (85 mL). Triethylamine (5.73 mL, 41.2 mmol) was added, and the mixture was cooled to -78 °C. Trifluoromethanesulfonic anhydride (4.15 mL, 24.7 mmol) was slowly added dropwise, and the mixture was stirred at -78 °C for 1 hour. The reaction was then quenched by slow dropwise addition of water under ice bath conditions. Extraction with dichloromethane was performed, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was purified by silica gel column chromatography to give a brown solid, 004-11 (1.15 g, 44% yield). LCMS: [M+H] + =315.1.

[0420] Compound 004-12:

[0421]

[0422] In a 50 mL single-necked flask, 004-11 (850 mg, 2.71 mmol), benzophenone imine (981 mg, 5.42 mmol), cesium carbonate (1.76 g, 5.42 mmol), tris(dibenzylacetone)dipalladium (376 mg, 0.41 mmol), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (474 ​​mg, 0.82 mmol) were added, followed by the addition of anhydrous 1,4-dioxane (27 mL). After purging three times with nitrogen, the mixture was stirred overnight at 110 °C. The reaction solution was concentrated and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography to give a yellow oily compound 004-12 (450 mg, 48% yield). LCMS: [M+H] + =346.1.

[0423] Compound 004-13:

[0424]

[0425] Compound 004-12 (450 mg, 1.30 mmol) was dissolved in 12 mL of 2N 1,4-dioxane hydrogen chloride solution and stirred at room temperature for 1 hour. The concentrated solution was then used directly in the next reaction step. LCMS: [M+H] + =182.1.

[0426] Compound 004-14:

[0427]

[0428] Compound 004-14 (442 mg, 2.44 mmol), 2,4,5-trichloropyrimidine (1.34 g, 7.32 mmol), and N,N-diisopropylethylamine (1.88 g, 14.64 mmol) were dissolved in 20 mL of anhydrous ethanol and refluxed overnight. The reaction solution was concentrated and purified by silica gel column chromatography to give a yellow oily compound 004-14 (220 mg, yield 27%). LCMS: [M+H] + =328.1.

[0429] Compound 004:

[0430]

[0431] Compound 004-14 (50 mg, 0.153 mmol) and intermediate B1 (59 mg, 0.184 mmol) were dissolved in 1.5 mL of tert-butanol, and methanesulfonic acid (88 mg, 0.918 mmol) was added with stirring. The reaction mixture was refluxed at 90 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and then a suitable amount of 2 mol / L hydrochloric acid aqueous solution was added. The mixture was extracted with dichloromethane. The aqueous phase was collected, and the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography. The purified mixture was then slurried with acetonitrile to obtain a light gray solid compound 004 (14.8 mg, yield: 15.8%). LCMS: [M+H] + =612.4.

[0432] 1 H NMR (400MHz, CDCl3): δ8.75(s,1H),8.37-8.33(m,1H),8.10(s,1H),8.05(s,1H), 7.46(t,J=8.0Hz,1H),7.35(s,1H),6.99(d,J=6.0Hz,1H),6.62(s,1H),3.85(s,3 H),3.30-3.12(m,3H),3.04-2.96(m,1H),2.67-2.60(m,6H),2.54-2.48(m,3H),2 .40-2.34(m,2H),2.32(s,3H),2.20(s,3H),1.97-1.94(s,2H),1.82-1.68(m,7H).

[0433] Example 26 Synthesis of target compound 005

[0434]

[0435] Compound 005:

[0436]

[0437] Intermediate C2 (70 mg, 0.21 mmol) was dissolved in 1 mL of tert-butanol, and intermediate B1 (68 mg, 0.21 mmol) and methanesulfonic acid (81.5 mg, 0.85 mmol) were added. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and then a suitable amount of 2 mol / L hydrochloric acid aqueous solution was added. The mixture was extracted with dichloromethane. The aqueous phase was collected, and the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography to obtain compound 005. LCMS: [M+H]+ = 612.4.

[0438] 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 8.34(s,1H),8.28(s,1H),8.24-8.19(m,1H),8.18(s,1H),7.50(t,J=7.8H z,1H),7.41(s,1H),7.24(d,J=7.6Hz,1H),6.73(s,1H),3.78(s,3H),3.73 -3.69(m,2H),3.38(s,2H),3.12-3.10(m,2H),2.69-2.52(m,6H),2.19-2. 12(m,5H),1.89(s,3H),1.86(s,3H),1.63-.160(m,2H),1.58-1.55(m,2H).

[0439] Example 27 Synthesis of target compound 006

[0440]

[0441] Compound 007-1:

[0442]

[0443] Intermediate A2 (290 mg, 1.94 mmol) was dissolved in 10 mL of ethanol, and 2,4,5-trichloropyrimidine (711 mg, 3.88 mmol) and N,N-diisopropylethylamine (1.28 mL, 7.76 mmol) were added. The reaction mixture was refluxed and stirred overnight. After the reaction was complete, the reaction mixture was concentrated and purified by column chromatography to obtain compound 007-1.

[0444] Compound 007-2:

[0445]

[0446] Compound 007-1 (390 mg, 1.32 mmol) was dissolved in 2 mL of acetic acid, and sodium perborate (1.01 g, 6.6 mmol) was added. The reaction mixture was stirred at 60 °C for one hour. After the reaction was complete, the mixture was concentrated and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate solution and brine, dried, filtered, and the crude product was concentrated and subjected to column chromatography to obtain compound 007-2.

[0447] Compound 007:

[0448]

[0449] Compound 007-2 (55 mg, 0.17 mmol) was dissolved in 1 mL of tert-butanol, and intermediate B1 (54 mg, 0.17 mmol) and methanesulfonic acid (65 mg, 0.68 mmol) were added. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, concentrated, and then a suitable amount of 2 mol / L hydrochloric acid aqueous solution was added. The mixture was extracted with dichloromethane. The aqueous phase was collected, and the pH was adjusted to alkaline by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted three times with dichloromethane. The combined organic phases were washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by reversed-phase preparative chromatography to obtain compound 007. LCMS: [M+H]+ = 610.4.

[0450] 1 H NMR(400MHz,DMSO-d6)δppm 8.30(s,1H),8.21(s,1H),8.06(s,1H),8.01-7.99(m,1H),7.68(d,J=7.2Hz,1H),7.60-7.56(m,1H),7.42-7.38(m,3H),6.68(s, 1H),3.77(s,3H),3.07-3.05(m,2H),2.68-2.55(m,10H),2.35-2.31(m,4H),2.02(s,3H),1.87-1.82(m,2H),1.59-1.56(m,2H).

[0451] Example 28 Synthesis of target compound 007

[0452]

[0453] Compound 007:

[0454]

[0455] Intermediate B3 (364 mg, 0.93 mmol) and intermediate C2 (320 mg, 0.93 mmol) were dissolved in 10 mL of n-butanol. Methanesulfonic acid (357 mg, 3.72 mmol) was added to the mixture, and the reaction was carried out at 100 °C. After cooling to room temperature, the mixture was concentrated, and an appropriate amount of water was added. The mixture was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solutions were dried, concentrated, and purified by reversed-phase column chromatography to obtain 30 mg of a white solid.

[0456] 1 H NMR (400MHz, DMSO-d6) δ8.31(d,J=12Hz,2H),8.21-8.14(m,2H),7.46(t,J=4.0Hz,1H),7.37(d,J=8 .0Hz,3H),7.20(d,J=8.0Hz,1H),6.75(s,1H),3.74(s,3H),3.69(t,J=8.0Hz,2H),3.40-3.36(m,1H) ,3.33-3.37(m,2H),3.01(d,J=12Hz,2H),2.67(t,J=12.0Hz,2H),2.60-2.53(m,2H),2.49-2.40(m, 3H), 2.40-2.22 (m, 5H), 2.16 (s, 3H), 1.85 (d, J = 12Hz, 2H), 1.64-1.46 (m, 4H), 0.61 (t, J = 8.0Hz, 2H).

[0457] Example 29 Synthesis of target compound 008

[0458]

[0459] Compound 008-2:

[0460]

[0461] Indole (1.28 g, 10.92 mmol) was dissolved in 6 mL of THF and stirred at 0 °C. 3.64 mL of 3 M methylmagnesium bromide tetrahydrofuran solution was slowly added dropwise. The reaction mixture was stirred at 0 °C for 30 min, and 2,4,5-trichloropyrimidine (0.63 mL, 10.92 mmol) was rapidly added to the system, with stirring continued for 5 min. The temperature of the reaction mixture was raised to 60 °C and stirred for 1.5 h. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with 5 mL of acetic acid. The reaction mixture was concentrated, extracted to obtain the crude product, and purified by column chromatography to obtain compound 008-2.

[0462] Compound 008-3:

[0463]

[0464] Dissolve 008-2 (750 mg, 2.85 mmol) in 10 mL of DMF. Add NaH (228 mg, 5.7 mmol) in an ice bath and stir at 0°C for 30 min. Then add methanesulfonyl chloride (490 mg, 4.3 mmol) dropwise. Stir the reaction mixture overnight at room temperature. Add an appropriate amount of water to the reaction mixture and extract three times with ethyl acetate. Combine the organic phases and wash three times with saturated brine. Dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (dichloromethane:methanol = 50:1) to give 200 mg of a white solid. LCMS: [M+H] + =342.2.

[0465] Compound 008:

[0466]

[0467] Compound 008-3 (200 mg, 0.6 mmol) and intermediate B3 (234 mg, 0.6 mmol) were dissolved in 20 mL of n-butanol, and methanesulfonic acid (230 mg, 2.4 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated, and purified by preparative column chromatography to obtain 22 mg of a white solid. LCMS: [M+H] + =696.3.

[0468] 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),8.50(d,J=2.8Hz,1H),8.23(s,1H),7.89(d,J=8.4,1H ),7.44(t,J=7.6Hz,1H),7.36(d,J=3.2Hz,3H),7.22(t,J=7.2Hz,1H),6.78(s,1H),3.73(s ,3H),3.60(s,3H),3.06(d,J=13.2Hz,2H),2.68(t,J=11.6Hz,2H),2.60-2.38(m,6H),2.33 -2.26(m,5H),2.15(s,3H),1.87(d,J=8.4Hz,2H),1.62-1.52(m,4H),0.61(t,J=7.6Hz,2H).

[0469] Example 30 Synthesis of target compound 009

[0470]

[0471] Compound 009:

[0472]

[0473] Intermediate C3 (60 mg, 0.21 mmol) and intermediate B1 (100 mg, 0.31 mmol) were dissolved in 10 mL of tert-butanol, and methanesulfonic acid (80 mg, 0.84 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solutions were dried, concentrated, and purified by reversed-phase column chromatography to obtain 25.5 mg of a white solid.

[0474] 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),8.25(s,1H),8.08(s,1H),8.01(d,J=4.0Hz,1H),7.48-7 .37(m,2H),7.10(d,J=4.0Hz,1H),6.69(s,1H),3.77(s,3H),3.63(s,2H),3.12-2.95(m,4H),2 .71-2.57(m,3H),2.48-2.43(m,2H),2.41-2.22(m,7H),2.17(s,3H),2.08(s,4H),1.85(d,J=8 .0Hz,2H),1.64-1.48(m,2H),2.35(s,3H),2.18(s,3H),2.01–1.89(m,2H),1.81–1.62(m,2H).

[0475] Example 31 Synthesis of target compound 010

[0476]

[0477] Compounds 010-1 and 010-1':

[0478]

[0479] Intermediate A3 (500 mg, 3.0 mmol) and 2,4-dichloro-5-cyanopyrimidine (626 mg, 3.6 mmol) were dissolved in 10 mL of tert-butanol, and N,N-diisopropylethylamine (930 mg, 7.2 mmol) was added. The reaction mixture was reacted at room temperature for 3 hours. After the reaction was completed, the solution was concentrated and purified by column chromatography (dichloromethane / methanol = 100:2) to give 530 mg of a pale yellow solid. This solid was then purified by reversed-phase chromatography (acetonitrile / water = 55%) to give isomers 010-1 (125 mg) and 010-1' (80 mg).

[0480] Compound 010-2:

[0481]

[0482] Under nitrogen protection, compound 010-1 (125 mg, 0.41 mmol) was dissolved in 5 mL of acetic acid, and sodium perborate tetrahydrate (318 mg, 2.1 mmol) was added. The reaction was carried out at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched with an aqueous sodium bisulfite solution, extracted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate and brine. The solution was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 100:1) to give 120 mg of a brown solid.

[0483] Compound 010:

[0484]

[0485] Compound 010-2 (120 mg, 0.36 mmol) and intermediate B1 (138 mg, 0.43 mmol) were dissolved in 6 mL of tert-butanol, and methanesulfonic acid (207 mg, 2.16 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solutions were dried, concentrated, and purified by reversed-phase column chromatography to obtain 11.0 mg of a white solid.

[0486] 1H NMR (400MHz, CDCl3) δ9.22(s,1H),8.39(s,1H),8.16(d,J=8.0Hz,1H),7.95(s,1H),7.82(s,1H),7.45(t,J=8.0Hz,1H,7.07(d,J=8.0Hz,1H),6 .61(s,1H),3.77(s,3H),3.88(s,3H),3.53-3.44(m,2H),3.21-3.06(m ,4H),2.84-2.46(m,12H),2.36(s,4H),2.16-1.92(m,5H),1.75(m,2H).

[0487] Example 32 Synthesis of target compound 011

[0488]

[0489] Compound 011-1: Compound 011-1':

[0490] Intermediate A3 (600 mg, 2.17 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (940 mg, 4.33 mmol) were dissolved in 15 mL of tert-butanol, and N,N-diisopropylethylamine (1.1 g, 8.68 mmol) was added. The reaction solution was reacted overnight at 80 °C. After the reaction was completed, the solution was concentrated and purified by column chromatography (dichloromethane / methanol = 100:2) to give 700 mg of a pale yellow solid, which was then purified by reversed-phase chromatography (acetonitrile / water = 55%) to give 011-1 (180 mg) and 011-1' (470 mg).

[0491] Compound 011-2:

[0492]

[0493] Under nitrogen protection, compound 011-1 (180 mg, 0.522 mmol) was dissolved in 5 mL of acetic acid, and sodium perborate tetrahydrate (401 mg, 2.6 mmol) was added. The reaction was carried out at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched with an aqueous sodium bisulfite solution, extracted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate aqueous solution and brine. After drying with anhydrous sodium sulfate, the solution was filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 100:1) to give 168 mg of a brown solid.

[0494] Compound 011:

[0495]

[0496] Compound 011-2 (168 mg, 0.44 mmol) and intermediate B1 (214 mg, 0.67 mmol) were dissolved in 6 mL of tert-butanol, and methanesulfonic acid (259 mg, 2.70 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solutions were dried, concentrated, and purified by reversed-phase column chromatography to obtain 60.0 mg of a white solid.

[0497] 1 H NMR (400MHz, DMSO-d6) δ12.35(s,1H),9.71(d,J=32.0Hz,1H),7.74-7.49(m,2H),7.41-7.23(m,2H),7.20-5.82(m,7H),3.82(s,4 H),3.76(d,J=12.0Hz,2H),3.84(s,3H),3.67-3.42(m,7H),3.00-2.88(m,1H),2.84(s,3H),2.34-2.20(m,4H),2.18-1.95(m,4H).

[0498] Example 33 Synthesis of target compound 012

[0499]

[0500] Compound 012-1:

[0501]

[0502] Intermediate A1 (70 mg, 0.46 mmol) and 2,4-dichloro-5-bromopyrimidine (210 mg, 0.92 mmol) were dissolved in 5 mL of ethanol, and N,N-diisopropylethylamine (237 mg, 1.84 mmol) was added. The reaction mixture was refluxed at 80 °C overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 90 mg of a yellow solid. LCMS: [M+H] + =342.5.

[0503] Compound 012-2:

[0504]

[0505] Compound 012-1 (90 mg, 0.26 mmol) was dissolved in 3 mL of acetic acid, and sodium perborate (203 mg, 1.32 mmol) was added. The reaction solution was reacted at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched with an aqueous sodium bisulfite solution, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give 110 mg of a brownish-yellow solid. LCMS: [M+H] + =374.3.

[0506] Compound 012:

[0507]

[0508] Compound 012-2 (100 mg, 0.26 mmol) and intermediate B1 (126 mg, 0.4 mmol) were dissolved in 5 mL of tert-butanol, and methanesulfonic acid (101.4 mg, 1.06 mmol) was added with stirring. The reaction mixture was refluxed at 90 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The solution was extracted three times with dichloromethane, and the organic phase was washed three times with saturated brine. The solution was dried over anhydrous sodium sulfate, concentrated, and purified by reversed-phase chromatography using a preparative column to obtain 40 mg of a white solid. LCMS: [M+H] + =654.3.

[0509] 1 H NMR(400MHz,DMSO-d6)δ12.38(s,1H),12.15(s,1H),9.28(s,1H),9.17(s,1H),8.44(s,1H),8.44( s,1H),7.89(s,1H),7.62(t,J=8.4Hz,1H),7.41(d,J=7.6Hz,1H),7.28(s,1H),6.74(s,1H),3.79(s ,3H),3.75(d,J=8.0Hz,4H),3.66(t,J=7.2Hz,2H),3.56(d,J=8.0Hz,4H),3.37(t,J=6.8Hz,2H),3 .22(d,J=6.8Hz,2H),2.85(s,3H),2.74(s,2H),2.33-2.21(m,3H),2.03(s,3H),1.99-1.93(m,2H).

[0510] Example 34 Synthesis of target compound 013

[0511]

[0512] Compound 013-2:

[0513]

[0514] Under nitrogen protection, 12.0 g (64.7 mmol) of 5-chloro-2-nitrobenzaldehyde and 4.6 g (74.1 mmol) of ethylene glycol were dissolved in 100 mL of toluene, and 0.6 g (3.2 mmol) of p-toluenesulfonic acid were added. The reaction solution was refluxed at 130 °C for 12 hours to remove water. After the reaction solution cooled to room temperature, an appropriate amount of water was added, and the pH was adjusted to alkaline with saturated sodium bicarbonate solution. The solution was extracted three times with ethyl acetate. The organic phase was collected, washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 14.0 g of crude brown liquid, which was used directly in the next reaction.

[0515] 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.6Hz,1H),7.79(d,J=2.3Hz,1H),7.46(dd,J=8.6,2.3Hz,1H),6.48(s,1H),4.17–3.96(m,4H).

[0516] Compound 013-3:

[0517]

[0518] Under nitrogen protection, compound 013-2 (1.0 g, 5.4 mmol) was dissolved in 10 mL of dry DMF, and 1-methyl-4-(piperidin-4-yl)piperazine (1.2 g, 6.5 mmol) and potassium carbonate (1.5 g, 10.8 mmol) were added. The reaction mixture was reacted at 120 °C for 3 hours. After the reaction solution cooled to room temperature, it was poured into water, extracted three times with dichloromethane, and the organic phase was collected. The organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 3%) to give 1.2 g of a yellow solid.

[0519] LCMS: [M+H] + =378.32.

[0520] Compound 013-4:

[0521]

[0522] Compound 013-3 (1.2 g, 3.2 mmol) was dissolved in 20 mL of methanol, and 10% wet palladium on carbon (120.0 mg) was added. The gas in the reaction flask was replaced with a hydrogen balloon, and the reaction was carried out at room temperature for 5 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to give 1.0 g of yellow solid, which was directly used in the next step of the reaction.

[0523] 1H NMR (400MHz, CDCl3) δ6.98(s,1H),6.81(d,J=8.5Hz,1H),6.61(d,J=8.5Hz,1H ),5.79(s,1H),4.17–4.00(m,4H),3.87(s,2H),3.51(d,J=11.5Hz,2H),2.71– 2.54(m,7H),2.48(s,3H),2.37–2.31(m,1H),2.29(s,3H),1.90(d,J=11.9Hz,2H),1.68(dd,J=23.6,11.9Hz,2H).

[0524] Compound 013-5

[0525]

[0526] Compound 013-4 (200 mg, 0.56 mmol), intermediate C1 (132 mg, 0.40 mmol), tris(dibenzylacetone)dipalladium (36 mg, 0.04 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (36 mg, 0.06 mmol), and sodium tert-butoxide (76 mg, 0.80 mmol) were dissolved in 10 mL of dry 1,4-dioxane and reacted at 110 °C for 20 hours under nitrogen protection. After cooling to room temperature, the reaction solution was poured into water, extracted three times with dichloromethane, and the organic phase was collected. The solution was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 20:1) to give 80 mg of a yellow solid. LCMS: [M+H] + =656.04.

[0527] Compound 013:

[0528]

[0529] Compound 013-5 (80 mg, 0.12 mmol) was dissolved in 5 mL of a tetrahydrofuran / water mixture (5:1). 0.1 mL of concentrated hydrochloric acid was slowly added dropwise, and the reaction was allowed to proceed overnight at room temperature. After the reaction was complete, a saturated sodium carbonate aqueous solution was added to adjust the pH to approximately 10–11. The mixture was extracted three times with dichloromethane, and the organic phase was collected. The phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by thin-layer chromatography (dichloromethane / methanol = 5:1) to give 16 mg of a yellow solid.

[0530] 1H NMR (400MHz, CDCl3) δ10.72 (s, 1H), 9.88 (s, 1H), 9.13 (s, 1H), 8.57 (d, J = 9.1Hz, 1H), 8.28 (d,J=8.3Hz,1H),8.18(s,1H),7.48(t,J=8.0Hz,1H),7.16-7.08(m,2H),7.02(d,J=7.7Hz ,1H),3.65(d,J=11.8Hz,2H),3.50-3.41(m,2H),3.07(t,J=6.2Hz,2H),2.77-2.62(m,6H) ,2.56-2.44(m,5H),2.44-2.35(m,2H),2.32(s,3H),2.02-1.93(m,2H),1.77-1.63(m,2H).

[0531] Example 35 Synthesis of target compound 014

[0532]

[0533] Compound 014-2:

[0534]

[0535] Compound 014-1 (3 g, 19.1 mmol) and 2-iodopropane (6.5 g, 38.2 mmol) were dissolved in 40 mL of acetone, and potassium carbonate (6.6 g, 47.7 mmol) was added. The reaction mixture was reacted overnight at 60 °C under nitrogen protection. After the reaction mixture was cooled to room temperature, it was concentrated, extracted, and purified by column chromatography (dichloromethane / methanol = 1 / 20) to give 2.6 g of a yellow solid, yield: 68%.

[0536] Compound 014-3:

[0537]

[0538] Compound 014-2 (1.5 g, 7.5 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.5 g, 8.3 mmol) were dissolved in 10 mL of N,N-dimethylformamide, and potassium carbonate (3.1 g, 22.6 mmol) was added. The reaction solution was reacted overnight at 60 °C under nitrogen protection. After the reaction solution was cooled to room temperature, it was added to 50 mL of water, extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane / methanol = 1 / 15) to give 1.9 g of a yellow solid, yield: 70%, LCMS: [M+H] + =363.3.

[0539] Compound 014-4:

[0540]

[0541] Compound 014-3 (1 g, 2.76 mmol) was dissolved in 20 mL of methanol, and 10% wet palladium on carbon (100 mg) was added. The mixture was hydrogenated at atmospheric pressure for 3 hours. After the reaction was complete, the reaction solution was filtered directly, and the filtrate was concentrated to give 850 mg of a deep purple solid. Yield: 93%. LCMS: [M+H] + =333.3.

[0542] Compound 014:

[0543]

[0544] Compound 014-4 (400 mg, 1.2 mmol) and intermediate C1 (640 mg, 1.6 mmol) were dissolved in 20 mL of tert-butanol, and methanesulfonic acid (693 mg, 7.2 mmol) was added with stirring. The reaction mixture was reacted at 90 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the pH was adjusted to 1–2 with hydrochloric acid solution. The mixture was extracted three times with ethyl acetate to remove impurities. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and a solid was obtained. The solid was slurried twice with acetonitrile to give 190 mg of a white solid product, yield: 25%. LCMS: [M+H] + =642.3.

[0545] 1 H NMR (400MHz, CDCl3) δ9.09 (s, 1H), 8.28 (d, J = 8.3Hz, 1H), 8.19-7.96 (m, 2H), 7.43-7.36 (m, 2H ),7.00(d,J=7.7Hz,1H),6.53(d,J=2.4Hz,1H),6.40-6.37(m,1H),4.56-4.53(m,1H),3.61(d ,J=11.9Hz,3H),3.49-3.38(m,2H),3.06(t,J=6.3Hz,2H),2.90(s,7H),2.67(t,J=11.5Hz,2H ),2.50-2.47(m,6H),2.0-1.98(m,2H),1.75-1.73(m,2H),1.36(d,J=6.1Hz,6H),1.24(s,1H).

[0546] Example 36 Synthesis of target compound 015

[0547]

[0548] Compound 015-1:

[0549]

[0550] Intermediate A3 (500 mg, 3.0 mmol) and 2,4-dichloropyrimidine (451 mg, 3.0 mmol) were dissolved in 10 mL of ethanol, and triethylamine (727 mg, 7.2 mmol) was added. The reaction mixture was reacted overnight at 80 °C. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (dichloromethane / methanol = 2%) to give 140 mg of a yellow solid. LCMS: [M+H] + =278.07.

[0551] Compound 015-2:

[0552]

[0553] Under nitrogen protection, compound 015-1 (140 mg, 0.50 mmol) was dissolved in 5 mL of acetic acid, and sodium perborate tetrahydrate (385 mg, 2.5 mmol) was added. The reaction was carried out at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched with sodium bisulfite aqueous solution, extracted with dichloromethane, and the organic phase was washed successively with saturated sodium bicarbonate aqueous solution and saturated brine. The phase was dried, filtered, concentrated, and purified by column chromatography (dichloromethane / methanol = 1%) to give 110 mg of brown solid.

[0554] 1 H NMR (400MHz, CDCl3) δ8.60(s,1H),8.19(d,J=5.8Hz,1H),7.96(d,J=8.2Hz,1H),7.47(t,J=8.0Hz,1H),7.03(d ,J=7.7Hz,1H),6.63(d,J=5.8Hz,1H),3.49–3.37(m,2H),3.05(t,J=6.3Hz,2H),2.47(dt,J=12.5,6.3Hz,2H).

[0555] Compound 015:

[0556]

[0557] Compound 015-2 (110 mg, 0.36 mmol) and intermediate B1 (170 mg, 0.53 mmol) were dissolved in 10 mL of tert-butanol, and methanesulfonic acid (208 mg, 2.16 mmol) was added with stirring. The reaction solution was reacted at 85 °C for 2 days. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated. An appropriate amount of water was added to the reaction solution, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The solution was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The solution was dried, concentrated, and purified by reversed-phase column chromatography to obtain 21.0 mg of a white solid.

[0558] 1 H NMR (400MHz, CDCl3) δ8.44 (s, 1H), 8.21 (d, J = 8.3Hz, 1H), 8.11-8.04 (m, 2H), 7.46-7.34 ( m,2H),6.91(d,J=7.7Hz,1H),6.60(s,1H),6.16(d,J=5.7Hz,1H),3.84(s,3H),3.49-3.3 8(m,2H),3.14(d,J=11.7Hz,2H),3.04(t,J=6.2Hz,2H),2.57(ddd,J=24.7,18.7,15.9Hz ,12H),2.43-2.38(m,1H),2.35(s,3H),2.18(s,3H),2.01-1.89(m,2H),1.81-1.62(m,2H)

[0559] Example 37 Synthesis of target compound 016

[0560]

[0561] Compound 016:

[0562]

[0563] Intermediate B5 (150 mg, 0.58 mmol) and intermediate C1 (200 mg, 0.58 mmol) were dissolved in 10 mL of tert-butanol, and methanesulfonic acid (223 mg, 3.49 mmol) was added with stirring. The reaction mixture was reacted at 90 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the pH was adjusted to 1–2 with hydrochloric acid solution. The mixture was extracted three times with ethyl acetate to remove impurities. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and a solid was obtained. High-performance liquid chromatography (HPLC) was used to prepare a white solid product of 50 mg, yield: 15%. LCMS: [M+H] + =571.3.

[0564] 1 H NMR(400MHz,D2O)δ7.98(s,1H),7.38-7.21(m,4H),7.01(s,1H),3.79(s,3H),3.70- 3.66(m,5H),3.50-3.47(m,2H),2.99-2.94(m,8H),2.50-2.23(m,6H),1.98(s,3H).

[0565] Example 38 Synthesis of target compound 017

[0566]

[0567] Compound 017-1:

[0568]

[0569] Compound 033-1 (1 g, 5.4 mmol) and N,N,N'-trimethylethylenediamine (0.8 g, 8.1 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and potassium carbonate (2.2 g, 16.2 mmol) was added. The reaction solution was reacted overnight at 110 °C under nitrogen protection. After the reaction solution was cooled to room temperature, it was added to 100 mL of water, extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane / methanol = 15:1) to give 510 mg of a yellow oily solid, yield: 35%, LCMS: [M+H] + =268.1.

[0570] Compound 017-2:

[0571]

[0572] Compound 017-1 (400 mg, 1.68 mmol) was dissolved in 20 mL of methanol, and 40 mg of 10% wetted palladium on carbon was added. The reaction was carried out under normal pressure for 3 hours. After the reaction was completed, the reaction solution was filtered directly, and the filtrate was concentrated to give 370 mg of a dark purple solid product. Yield: 91%. LCMS: [M+H] + =238.1.

[0573] Compound 017:

[0574]

[0575] Compound 017-3 (140 mg, 0.58 mmol) and intermediate C1 (200 mg, 0.58 mmol) were dissolved in 20 mL of tert-butanol, and methanesulfonic acid (223 mg, 3.49 mmol) was added with stirring. The reaction mixture was reacted at 90 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the pH was adjusted to 1–2 with hydrochloric acid solution. The mixture was extracted three times with ethyl acetate to remove impurities. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and a solid was obtained. High-performance liquid chromatography (HPLC) was used to prepare a white solid product of 90 mg, yield: 28%. LCMS: [M+H] + =545.3.

[0576] 1 H NMR(400MHz,D2O)δ8.12(s,1H),7.55(t,J=7.9Hz,1H),7.42(d,J=7.8Hz,1H),7.33(d,J=7.8Hz,1H),7.26(s,1H),6.97(s,1H),3.81(s,3H) ,3.63(t,J=7.0Hz,2H),3.58-3.48(m,2H),3.27(t,J=7.0Hz,2H),3.06(t,J=6.1Hz,2H),2.88-2.85(m,9H),2.41-2.28(m,2H),2.01(s,3H).

[0577] Example 39 Synthesis of target compound 018

[0578]

[0579] Compound 018-1:

[0580]

[0581] Compound 033-1 (1 g, 5.4 mmol) and N-methylpiperazine (0.7 g, 7.0 mmol) were dissolved in 20 mL of N,N-dimethylformamide, and potassium carbonate (2.2 g, 16.2 mmol) was added. The reaction solution was reacted overnight at 65 °C under nitrogen protection. After the reaction solution was cooled to room temperature, it was added to 100 mL of water, extracted with ethyl acetate, washed with saturated brine, concentrated, and purified by column chromatography (dichloromethane / methanol = 15:1) to give 420 mg of a yellow solid, yield: 31%, LCMS: [M+H] + =266.1.

[0582] Compound 018-2:

[0583]

[0584] Compound 018-1 (430 mg, 1.62 mmol) was dissolved in 20 mL of methanol, and 10% wet palladium on carbon (43 mg) was added. The reaction was carried out under normal pressure for 3 hours. After the reaction was completed, the reaction solution was filtered directly, and the filtrate was concentrated to give 390 mg of a dark purple solid product. Yield: 99%. LCMS: [M+H] + =237.4.

[0585] Compound 018:

[0586]

[0587] Compound 018-3 (200 mg, 0.85 mmol) and intermediate C1 (380 mg, 1.1 mmol) were dissolved in 20 mL of tert-butanol, and methanesulfonic acid (490 mg, 5.08 mmol) was added with stirring. The reaction mixture was reacted at 90 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the pH was adjusted to 1–2 with hydrochloric acid solution. The mixture was extracted three times with ethyl acetate to remove impurities. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and a solid was obtained. High-performance liquid chromatography (HPLC) was used to prepare 80 mg of a white solid product, yield: 17%. LCMS: [M+H] + =543.3.

[0588] 1 H NMR (400MHz, CDCl3) δ9.14 (s, 1H), 8.32 (d, J = 8.3Hz, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.47– 7.35(m,2H),6.97(d,J=7.6Hz,1H),6.64(s,1H),3.84(s,3H),3.54-3.38(m,3H),3.06( t,J=6.3Hz,2H),2.94(m,4H),2.63(s,3H),2.50-2.47(m,2H),2.40(s,3H),2.14(s,3H).

[0589] Example 40 Synthesis of target compound 019

[0590]

[0591] Compound 019-2:

[0592]

[0593] Compound 019-1 (10.0 g, 37.45 mmol), 3-mercaptopropionic acid (4.4 g, 41.20 mmol), and potassium carbonate (7.8 g, 56.18 mmol) were dissolved in DMF (300 mL) and stirred at room temperature for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction solution was poured into water, and the pH was adjusted to 5 with 4 mol / L HCl. The mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethanol to give 12.0 g (91% yield) of a yellow solid, compound 019-2. LCMS (ESI): 354 (M+H) + .

[0594] Compound 019-3:

[0595]

[0596] Compound 019-2 (3.2 g, 9.07 mmol) and DMF (0.1 mL) were dissolved in dichloroethane (30 mL), and thionyl chloride (1.1 g, 9.52 mmol) was added dropwise at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the mixture was added dropwise to dichloroethane (30 mL) containing aluminum trichloride (1.6 g, 11.79 mmol) at 0 °C. The reaction mixture was brought to room temperature and stirred for 4 hours. After the reaction was complete, it was cooled to room temperature and quenched slowly in ice water. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 2.3 g (76% yield) of a pale yellow solid, compound 019-3. LCMS (ESI): 336 (M+H) + .

[0597] Compound 019-4:

[0598]

[0599] Compound 019-3 (2.0 g, 5.97 mmol) was dissolved in methanol (60 mL). Sodium borohydride (824 mg, 17.91 mmol) was added in portions at 0 °C, and the mixture was stirred at 0 °C for 20 minutes. After the reaction was complete, the mixture was quenched with ice water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.9 g (94% yield) of a pale yellow solid, compound 019-4. LCMS (ESI): 338 (M+H) + .

[0600] Compound 019-5:

[0601]

[0602] Compound 019-4 (1.9 g, 5.64 mmol) was dissolved in methanol / water (80 mL, v / v = 1:1). Ammonium chloride (3.0 g, 56.38 mmol) and iron powder (1.6 g, 28.19 mmol) were added sequentially at room temperature, and the mixture was stirred at 60 °C for 1 hour. After cooling to room temperature, the mixture was filtered, methanol was removed under reduced pressure, and the solution was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.6 g (92% yield) of a yellow solid, compound 019-5. LCMS (ESI): 308 (M+H) + .

[0603] Compound 019-6:

[0604]

[0605] Compound 019-5 (1.6 g, 5.21 mmol) and triethylsilane (6.0 g, 52.12 mmol) were dissolved in trifluoroacetic acid (16 mL) and stirred at 60 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1.1 g (73% yield) of white solid compound 019-6. LCMS (ESI): 292 (M+H) + .

[0606] Compound 019-7:

[0607]

[0608] Compound 019-6 (1.1 g, 3.78 mmol), 2,4,5-trichloropyrimidine (2.1 g, 11.34 mmol), and N,N-diisopropylethylamine (1.5 g, 11.34 mmol) were dissolved in ethanol (15 mL) and stirred at 80 °C for 24 hours. After cooling to room temperature, the mixture was filtered and washed with ethanol to give 840 mg (51% yield) of compound 019-7 as a white solid. LCMS (ESI): 438 (M+H) + .

[0609] Compound 019-8:

[0610]

[0611] Compound 019-7 (440 mg, 1.01 mmol) and sodium perborate tetrahydrate (775 mg, 5.03 mmol) were added to acetic acid (10 mL) and heated at 60 °C for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 420 mg (89% yield) of a pale yellow solid, compound 019-8. LCMS (ESI): 470 (M+H) + .

[0612] Compound 019-9:

[0613]

[0614] Compound 019-8 (420 mg, 0.89 mmol), intermediate B4 (396 mg, 0.98 mmol), and methanesulfonic acid (515 mg, 5.36 mmol) were dissolved in tert-butanol (10 mL) and stirred at 85 °C for 48 hours. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 550 mg (74% yield) of gray solid compound 019-9. LCMS (ESI): 837 (M+H) + .

[0615] Compound 019-10:

[0616]

[0617] Compound 019-9 (550 mg, 0.66 mmol) and potassium hydroxide (553 mg, 9.87 mmol) were dissolved in methanol / water (15 mL, v / v = 3:1) and stirred at 90 °C for 24 hours. After the reaction was complete, the reaction solution was concentrated and extracted three times with dichloromethane / methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 420 mg (yield 85%) of gray solid compound 019-10. LCMS (ESI): 753 (M+H) + .

[0618] Compound 019:

[0619]

[0620] Compound 019-10 (200 mg, 0.27 mmol), palladium acetate (12 mg, 0.05 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (31 mg, 0.05 mmol), and sodium tert-butoxide (51 mg, 0.53 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred overnight at 85 °C under a nitrogen atmosphere. After the reaction was complete, the mixture was extracted three times with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase preparative chromatography to give 30 mg (yield 18%) of the gray solid compound 019.

[0621] LCMS (ESI): 625 (M+H) + .

[0622] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.37(s,1H),8.21(d,J=15.2Hz,1H),7.87(s,1H),7. 71(s,1H),7.55(d,J=1.9Hz,1H),6.72(d,J=1.8Hz,1H),6.60(s,1H),3.79(s,3H),3.52(d d,J=7.3,4.7Hz,3H),3.23(d,J=11.3Hz,2H),2.89(t,J=6.1Hz,2H),2.61(t,J=11.1Hz,3H ),2.51(s,3H),2.40-2.21(m,6H),2.16(s,3H),1.82(d,J=10.9Hz,2H),1.75-1.57(m,2H).

[0623] Example 41 Synthesis of target compound 020

[0624]

[0625] Compound 020-2:

[0626]

[0627] Under a nitrogen atmosphere, 5.0 g (25.0 mmol) of O20-1, 2.9 g (27.5 mmol) of 3-mercaptopropionic acid, and 6.9 g (50 mmol) of potassium carbonate were added to 50 mL of DMF. The reaction solution was reacted at room temperature for 1 h. After the reaction was completed, water was added, and the pH of the solution was adjusted to 6-7 with dilute hydrochloric acid. The solution was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and recrystallized from ethanol to give 6.5 g of yellow solid.

[0628] Compound 020-3:

[0629]

[0630] O20-2 (6.5 g, 22.8 mmol), thionyl chloride (5.38 g, 45.6 mmol), and DMF (0.5 mL) were added to 60 mL of 1,2-dichloroethane and reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated to remove thionyl chloride. The concentrated solution was then diluted with 1,2-dichloroethane and added dropwise to a solution of aluminum trichloride (4.55 g, 34.2 mmol) in 1,2-dichloroethane at 0 °C. The mixture was reacted at 65 °C for 3 hours. After the reaction was complete, the solution was cooled, poured into ice water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 2.4 g of a pale yellow solid.

[0631] Compound 020-4:

[0632]

[0633] Compound 020-3 (1.0 g, 3.74 mmol) was dissolved in 60 mL of methanol. Cobalt chloride hexahydrate (1.78 g, 7.48 mmol) was added at 0 °C, followed by sodium borohydride (1.4 g, 37.4 mmol) in portions. The solution was reacted at 0 °C for 1 h. After the reaction was complete, water was slowly added to quench the reaction mixture. The solution was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 350 mg of a pale yellow solid.

[0634] Compound 020-5:

[0635]

[0636] Compound 020-4 (350 mg, 1.46 mmol) and triethylsilane (1.69 g, 14.6 mmol) were added to 20 mL of trifluoroacetic acid. The solution was heated at 60 °C for 3 h. After the reaction was complete, the reaction solution was concentrated and neutralized to alkaline with saturated sodium bicarbonate solution. The solution was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 200 mg of a light brown solid.

[0637] Compound 020-6:

[0638]

[0639] Compound 020-5 (200 mg, 0.90 mmol), 2,4,5-trichloropyrimidine (330 mg, 1.8 mmol), and N,N-diisopropylethylamine (348 mg, 2.7 mmol) were added to 15 mL of ethanol. The solution was reacted overnight at 90 °C. After the reaction was complete, the solution was concentrated, and an appropriate amount of water was added to the reaction solution. The solution was extracted three times with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. The solution was filtered, concentrated, and purified by column chromatography to obtain 280 mg of a pale yellow solid.

[0640] Compound 020-7:

[0641]

[0642] Compound 020-6 (280 mg, 0.76 mmol) and sodium perborate tetrahydrate (580 mg, 3.8 mmol) were added to 15 ml of acetic acid. The solution was heated at 60 °C for 2 hours. After the reaction was complete, the solution was concentrated. An appropriate amount of water was added to the reaction solution, and the mixture was extracted three times with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 280 mg of a pale yellow solid.

[0643] Compound 020-8:

[0644]

[0645] Compound 020-7 (280 mg, 0.70 mmol), intermediate B4 (423 mg, 1.05 mmol), and methanesulfonic acid (403 mg, 4.2 mmol) were added to 10 mL of tert-butanol. The solution was heated at 85 °C overnight. After the reaction was complete, the solution was concentrated, adjusted to alkalinity with saturated sodium bicarbonate solution, and extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 850 mg of crude gray solid, which was then directly proceeded to the next step.

[0646] Compound 020-9:

[0647]

[0648] Compound 020-8 (850 mg, crude product) and potassium hydroxide (780 mg, 14 mmol) were added to 20 mL of methanol and 5 mL of water. The solution was heated at 85 °C overnight. After the reaction was complete, the reaction solution was concentrated, water was added, and then dilute hydrochloric acid was added to adjust the pH of the solution to neutral. The solution was then extracted three times with dichloromethane / methanol (10:1). The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 200 mg of gray solid.

[0649] Compound 020:

[0650]

[0651] Compound 020-9 (200 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol), and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) were added to 10 mL of DMF, followed by the addition of N,N-diisopropylethylamine (155 mg, 1.2 mmol). The solution was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and an appropriate amount of water was added. The solution was then extracted three times with dichloromethane / methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by reverse-phase preparative chromatography to obtain 12.8 mg of a white solid.

[0652] 1 H NMR (400MHz, DMSO-d6) δ9.22 (s, 1H), 8.86 (s, 1H), 8.59 (s, 1H), 8.19 (d, J = 4.0 Hz,1H),7.92(s,1H),7.52(s,1H),7.29-7.22(m,1H),6.43(s,1H),3.99-3.80 (m,2H),3.72(s,4H),3.65-3.58(m,5H),3.40-3.25(m,6H),3.00(t,J=4.0Hz, 2H),2.87(s,3H),2.64(t,J=12.0Hz,3H),2.27-2.15(m,3H),1.93-1.76(m,1H)

[0653] Example 42 Synthesis of target compound 021

[0654]

[0655] Compound 021-2:

[0656]

[0657] Compound 021-1 (9.5 g, 32 mmol), dimethoxyphosphine (2.84 g, 36.48 mmol), palladium acetate (0.43 g, 1.92 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (0.92 g, 1.6 mmol), and potassium phosphate (8.55 g, 40.32 mmol) were dissolved in DMF (190 mL) and stirred at 105 °C for 6 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was filtered, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate (400 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 8.5 g of a brown solid compound.

[0658] 1H-NMR (400Hz, CDCl3) δ6.90 (d, J = 13.2Hz, 1H), 6.78 (d, J = 12.8Hz, 2H), 5.52 (s, 2H), 1.76 (s, 3H), 1.72 (s, 3H).

[0659] Compound 021-3:

[0660]

[0661] Compound 021-2 (2 g, 7.54 mmol), 2,4,5-trichloropyrimidine (6.6 g, 36.26 mmol), and N,N-diisopropylethylamine (4.7 g, 36.45 mmol) were dissolved in tert-butanol (40 mL) and stirred overnight at 85 °C under nitrogen protection. After the reaction solution cooled to room temperature, it was filtered, and the resulting solid was dried under reduced pressure to give 1.7 g of a white product. LCMS: [M+H] + =396.1.

[0662] 1 H-NMR (400Hz, DMSO) δ12.04 (s, 1H), 8.79 (d, J = 5.2Hz, 1H), 8.50 (s, 1H), 7.65 (d, J =22Hz, 1H), 7.47 (d, J = 11.6Hz, 1H), 1.85 (d, J = 6.0Hz, 3H), 1.81 (d, J = 5.6Hz, 3H).

[0663] Compound 021-4:

[0664]

[0665] Compound 021-3 (500 mg, 1.27 mmol), intermediate B4 (560 mg, 1.39 mmol), and methanesulfonic acid (120 mg, 1.25 mmol) were dissolved in tert-butanol (17 mL) and stirred at 85 °C for 48 hours. After cooling to room temperature, the solution was concentrated under reduced pressure, and impurities were extracted with dichloromethane. The aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution and extracted with a dichloromethane:methanol mixture of 10:1. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 880 mg of the compound. LCMS: [M+H] + =762.9

[0666] Compound 021-5:

[0667]

[0668] Compound 021-4 (800 mg, 1.05 mmol) and potassium hydroxide (400 mg, 7.15 mmol) were dissolved in a methanol / water mixture (8 mL / 8 mL) and stirred overnight at 75 °C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, extracted with dichloromethane, and purified by silica gel column chromatography to give 650 mg of a white solid. LCMS: [M+H] + =677.6

[0669] Compound 021:

[0670]

[0671] Compound 021-5 (200 mg, 0.29 mmol), palladium acetate (13 mg, 0.058 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (33.5 mg, 0.058 mmol), and sodium tert-butoxide (55.47 mg, 0.58 mmol) were dissolved in 1,4-dioxane (5 mL). The mixture was stirred at 100 °C for 24 hours under nitrogen protection. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 120 mg of crude product. After preparative purification by high-performance liquid chromatography, 30 mg of a white solid was obtained. LCMS: [M+H] + =597.1

[0672] 1 H-NMR (400Hz, DMSO-d6) δ10.81(s,1H),8.21(d,J=5.2Hz,2H),8.10(s,1H),7.85(s,1H),7.64(s,1H),7.29(t,J=13.2Hz,1H),6.84(d,J =8.4Hz,1H),6.60(s,1H),3.79(s,3H),3.23(d,J=8.8Hz,2H),2.65(m,6H),2.48(m,5H),2.25(m,3H),1.85(d,J=10Hz,2H),1.71(m,8H).

[0673] Example 43 Synthesis of target compound 022

[0674]

[0675] Compound 022-2:

[0676]

[0677] Under a nitrogen atmosphere, compound 022-1 (10.0 g, 36.0 mmol), dimethylphosphine oxide (3.4 g, 43.3 mmol), palladium acetate (404 mg, 1.8 mmol), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, and potassium phosphate (9.2 g, 43.3 mmol) were added to 120 mL of DMF, and the reaction mixture was incubated overnight at 100 °C. After the reaction was complete, the mixture was filtered, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane / methanol = 50:1) to give 8.0 g of a brown solid.

[0678] Compound 022-3:

[0679]

[0680] Compound 022-2 (1.32 g, 5.8 mmol), 2,4,5-trichloropyrimidine (1.58 g, 8.7 mmol), and N,N-diisopropylethylamine (2.24 g, 17.4 mmol) were added to 25 mL of ethanol and reacted overnight at 85 °C. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and dried to obtain 1.37 g of a pale yellow solid.

[0681] Compound 022-4:

[0682]

[0683] Under nitrogen protection, compound 022-3 (1.2 g, 3.22 mmol), intermediate B4 (1.95 g, 4.83 mmol), and methanesulfonic acid (1.85 g, 19.32 mmol) were added to 20 mL of tert-butanol and reacted at 85 °C for 48 hours. After the reaction was complete, the reaction solution was concentrated, adjusted to alkalinity with sodium bicarbonate, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography (acetonitrile / water = 55%:45%) to give 1.4 g of a pale yellow solid.

[0684] Compound 022-5:

[0685]

[0686] Compound 022-4 (300 mg, 0.41 mmol) and potassium hydroxide (224 mg, 4 mmol) were added to 2 mL of methanol and 2 mL of water, and the solution was heated at 80 °C overnight. After the reaction was complete, the solution was adjusted to neutral and concentrated to obtain a crude product (500 mg), which was then directly used for the next reaction.

[0687] Compound 022:

[0688]

[0689] Compound 022-5 (263 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), and 1-hydroxybenzotriazole (111 mg) were added to 5 mL of DMF. Then, N,N-diisopropylethylamine (211 mg, 1.64 mmol) was added with stirring, and the mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was concentrated and purified by reverse-phase column chromatography (acetonitrile / water = 55%:45%) to give 67 mg of a light red solid.

[0690] 1 H NMR (400MHz, CDCl3) δ10.64(s,1H),8.47(s,1H), 8.09(s,1H), 8.02(s,1H), 7.79(s,1H),7.45(d,J=8.0Hz,1H),7.27-7.22(m,1H),7.03(s,1H),6.55(s, 1H),3.82(s,3H),3.09(d,J=8.0Hz,2H),2.78-2.60(m,5H),2.60-2.36(m,4H ),2.34(s,3H),1.98(d,J=12Hz,2H),1.81(s,3H),1.78(s,3H),1.72(s,4H).

[0691] Example 44 Synthesis of target compound 023

[0692]

[0693] Compound 023-1:

[0694]

[0695] Intermediate A2 (170 mg, 1.14 mmol) and 2,4,5-trichloropyrimidine (520 mg, 2.28 mmol) were dissolved in 8 mL of ethanol. N,N-diisopropylethylamine (441 mg, 3.42 mmol) was added, and the reaction mixture was refluxed at 80 °C overnight. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to give 200 mg of a yellow solid. LCMS: [M+H] + =296.5.

[0696] Compound 023:

[0697]

[0698] Compound 023-1 (100 mg, 0.34 mmol) and intermediate B1 (118 mg, 0.37 mmol) were dissolved in 3 mL of tert-butanol, and methanesulfonic acid (130.5 mg, 1.36 mmol) was added with stirring. The reaction mixture was reacted at 85 °C for 2 days. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The solution was extracted three times with dichloromethane, and the organic phases were combined and washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative column chromatography to obtain 100 mg of a white solid. LCMS: [M+H] + =578.2.

[0699] 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),10.74(s,1H),9.53(s,1H),7.97(d,J=8.0Hz,1H),7.79( d,J=5.2Hz,1H),7.57(d,J=5.6Hz,1H),7.50(t,J=7.6Hz,1H),7.42(d,J=7.6Hz,1H),6.96(s,1 H),6.64(s,1H),3.80(s,2H),3.76(s,3H),3.72-3.61(m,3H),3.39-3.37(m,4H),3.10-3.07(m ,3H),2.89(s,3H),2.71-2.51(s,2H),2.19-2.17(m,2H),1.93-1.87(m,2H),1.70-1.61(m,2H).

[0700] Example 45 Synthesis of target compound 024

[0701]

[0702] Compound 024:

[0703]

[0704] Intermediate B5 (95 mg, 0.36 mmol), intermediate C3 (100 mg, 0.25 mmol), and methanesulfonic acid (120 mg, 1.25 mmol) were dissolved in tert-butanol (4 mL) and stirred at 85 °C for 48 hours. After cooling to room temperature, the solution was concentrated under reduced pressure, extracted with dichloromethane, and the aqueous phase was adjusted to pH 8-9 with saturated sodium bicarbonate solution. The solution was then extracted with a 10:1 (v / v) mixture of dichloromethane and methanol. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 30 mg of compound O24. LCMS [M+H] +: 617.23.

[0705] 1 H-NMR (400Hz, CDCl3) δ9.05 (s, 1H), 8.27 (d, J = 5.2Hz, 1H), 8.21 (s, 1H), 7.99 (s, 1 H),7.44(t,J=16Hz,2H),7.00(d,J=8Hz,1H),6.61(s,1H),3.86(s,3H),3.48(m,J= 12.4Hz,2H),3.17(d,J=12Hz,2H),3.09(t,J=12.4Hz,2H),2.75(t,J=8Hz,2H),2. 67(t,J=22Hz,2H),2.42(s,7H),2.12(s,3H),2.00(d,J=12.4Hz,2H),1.75(m,2H).

[0706] Example 46 Synthesis of target compound 025

[0707]

[0708] Compound 025-1:

[0709]

[0710] Intermediate A1 (130 mg, 0.86 mmol) and 5-bromo-2,4-dichloropyrimidine (392 mg, 1.72 mmol) were dissolved in 10 mL of ethanol, and N,N-diisopropylethylamine (333 mg, 2.58 mmol) was added. The reaction solution was refluxed at 90 °C overnight. After the reaction solution was cooled to room temperature, it was concentrated and purified by column chromatography (dichloromethane / methanol = 50:1) to give 160 mg of a yellow solid.

[0711] Compound 025-2:

[0712]

[0713] Under nitrogen protection, compound 025-1 (160 mg, 0.47 mmol) was dissolved in 5 mL of acetic acid. Sodium perborate tetrahydrate (356 g, 2.33 mmol) was added at room temperature, and the reaction was carried out at 60 °C for 2 hours. After the reaction solution cooled to room temperature, the reaction was quenched by adding sodium bisulfite aqueous solution. The solution was concentrated and extracted with dichloromethane. The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain 160 mg of brown solid.

[0714] Compound 025:

[0715]

[0716] Compound 025-2 (100 mg, 0.27 mmol) and intermediate B5 (140 mg, 0.53 mmol) were dissolved in 10 mL of tert-butanol, and methanesulfonic acid (128 mg, 1.34 mmol) was added with stirring. The reaction mixture was refluxed at 85 °C overnight. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and the crude product was purified by reversed-phase column chromatography to give 16.0 mg of a white solid.

[0717] 1 H NMR(400MHz,DMSO-d6)δ8.49(d,J=4.0Hz,1H),8.39(s,1H),8.25(s,1H),8.03(s,1H),7.53 (t,J=4.0Hz,1H),7.40(s,1H),7.06(d,J=4.0Hz,1H),6.65(s,1H),3.88(s,3H),3.63(s,2H) ,3.58(t,J=8.0Hz,2H),3.42(t,J=8.0Hz,2H),3.19(d,J=12.0Hz,1H),2.68(t,J=12.0Hz,2H ),2.42(s,6H),2.41-2.33(m,1H),2.20(s,3H),1.99(d,J=12.0Hz,12H),1.80-1.68(m,2H).

[0718] Example 47 Synthesis of target compound 026

[0719]

[0720] Compound 026-1:

[0721]

[0722] Intermediate A2 (300 mg, 2.01 mmol) and 2,4-dichloro-5-bromopyrimidine (918 mg, 4.02 mmol) were dissolved in 15 mL of ethanol, and N,N-diisopropylethylamine (1.04 g, 8.04 mmol) was added. The reaction mixture was reacted overnight at 80 °C. After cooling to room temperature, the mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give 520 mg of a yellow solid. LCMS: [M+H] + =340.5.

[0723] Compound 026-2:

[0724]

[0725] Compound 026-1 (150 mg, 0.44 mmol) was dissolved in 3 mL of acetic acid and 3 mL of acetic anhydride, and hydrogen peroxide (2.47 mL, 2.82 mmol) was added. The reaction solution was reacted at 60 °C for 1 h. After the reaction solution cooled to room temperature, water was added to dilute the reaction mixture, and a white solid precipitated. Filtering yielded 130 mg of the white solid. LCMS: [M+H] + =372.3.

[0726] Compound 026:

[0727]

[0728] Compound 026-2 (130 mg, 0.36 mmol) and intermediate B5 (143 mg, 0.54 mmol) were dissolved in 5 mL of tert-butanol, and methanesulfonic acid (138 mg, 1.44 mmol) was added with stirring. The reaction mixture was reacted overnight at 85 °C. After the reaction was completed, the mixture was cooled to room temperature and concentrated. A suitable amount of water was added to the reaction mixture, and the solution was washed three times with dichloromethane. The aqueous phase was collected, and the pH was adjusted to 10–11 with saturated sodium carbonate solution. The solution was extracted three times with dichloromethane, and the organic phases were combined and washed three times with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative column reversed-phase chromatography to obtain 18 mg of a white solid. LCMS: [M+H] + =699.0.

[0729] 1 H NMR(400MHz,DMSO-d6)8.27(s,1H),8.22(s,1H),8.17(s,1H),8.07-8.04(m ,2H),7.67(d,J=6.8Hz,1H),7.53(t,J=7.6Hz,1H),7.42(d,J=7.2Hz,1H),7. 35(d,J=6.8Hz,2H),6.68(s,1H),3.75(s,3H),3.05(d,J=6.4Hz,2H),2.64-2 .54(m,3H),2.31(s,6H),2.04(s,3H),1.89-1.86(m,2H),1.58-1.56(m,2H).

[0730] Example 48 Synthesis of target compound 027

[0731]

[0732] Compound 027-2:

[0733]

[0734] 027-1 (10.0 g, 45.6 mmol), isopropanethiol (3.7 g, 48 mmol), and potassium carbonate (12.0 g, 91 mmol) were added to 150 mL of DMF, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 12.0 g of a yellow solid.

[0735] Compound 027-3:

[0736]

[0737] O27-2 (5.0 g, 18.2 mmol), ammonium chloride (9.6 g, 182 mmol), and iron powder (6.0 g, 109 mmol) were added to 50 mL of ethanol and 10 mL of water, and reacted at 60 °C for 2 hours. After the reaction was complete, the mixture was filtered, and the ethanol was removed by rotary evaporation. The residue was added to water, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.2 g of a brown solid.

[0738] Compound 027-4:

[0739]

[0740] Compound 027-3 (1.0 g, 4.1 mmol), 2,4,5-trichloropyrimidine (2.0 g, 12.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12.2 mmol) were dissolved in 15 mL of methanol and reacted overnight at 90 °C. After the reaction was completely cooled, the reaction solution was concentrated, water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 760 mg of a pale yellow solid.

[0741] Compound 027-5:

[0742]

[0743] Compound 027-4 (380 mg, 1.0 mmol) and sodium perborate tetrahydrate (770 mg, 5.0 mmol) were added to 20 mL of acetic acid and heated at 60 °C for 2 h. After the reaction was complete, the reaction solution was concentrated, neutralized to alkaline with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 410 mg of a pale yellow solid.

[0744] Compound 027-6:

[0745]

[0746] Compound 027-5 (410 mg, 0.97 mmol), intermediate B4 (483 mg, 1.2 mmol), and methanesulfonic acid (576 mg, 6.0 mmol) were added to 8 mL of tert-butanol and reacted overnight at 85 °C. After the reaction was complete, the reaction solution was concentrated and an appropriate amount of water was added. The pH was adjusted to alkaline with saturated sodium bicarbonate, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 840 mg of a brown solid. This solid was not purified and was directly used in the next experiment.

[0747] Compound 027-7:

[0748]

[0749] Compound 027-6 (840 mg, crude) and potassium hydroxide (1.3 g, 23.2 mmol) were added to 15 mL of methanol and 5 mL of water, and the solution was reacted at 85 °C for 48 hours. After the reaction was complete, the reaction solution was concentrated, an appropriate amount of water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 280 mg of a pale yellow solid.

[0750] Compound 027:

[0751]

[0752] Under a nitrogen atmosphere, compound 027-7 (180 mg, 0.25 mmol), palladium acetate (11.5 mg, 0.05 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (31.0 mg, 0.05 mmol), and sodium tert-butoxide (49.0 mg, 0.5 mmol) were added to 10 mL of 1,4-dioxane and reacted at 100 °C for 4 hours. After the reaction was complete, the mixture was cooled, concentrated, and a suitable amount of water was added. The mixture was then extracted three times with dichloromethane / methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, concentrated to obtain a crude product, and purified by reversed-phase preparative chromatography to give 30.5 mg of a white solid.

[0753] 1H NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.47(s,1H),8.21(s,1H),8.16(s,1H),7.81(s,1H),7.44(d,J=12.0Hz,1H),6.97-6.92(m,1H),6.62(s,1H) ,3.80(s,3H),3.31-3.19(m,3H),2.69-2.53(m,6H),2.47-2.27(m,5H),2 .19(s,3H),1.88-1.78(m,2H),1.77-1.63(m,2H),1.12(d,J=4.0Hz,6H).

[0754] Example 49 Synthesis of target compound 028

[0755]

[0756] Compound 028-2:

[0757]

[0758] 028-1 (10.0 g, 45.6 mmol), isopropanethiol (3.7 g, 48 mmol), and potassium carbonate (12.0 g, 91 mmol) were added to 150 mL of DMF, and the reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give 12.0 g of a yellow solid.

[0759] Compound 028-3:

[0760]

[0761] O28-2 (5.0 g, 18.2 mmol), ammonium chloride (9.6 g, 182 mmol), and iron powder (6.0 g, 109 mmol) were added to 50 mL of ethanol and 10 mL of water, and reacted at 60 °C for 2 hours. After cooling, the reaction solution was filtered, concentrated, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4.2 g of a brown solid.

[0762] Compound 028-4:

[0763]

[0764] Compound 028-3 (1.0 g, 4.1 mmol), 2,4,5-trichloropyrimidine (2.0 g, 12.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12.2 mmol) were dissolved in 15 mL of ethanol and reacted overnight at 90 °C. The reaction mixture was cooled and concentrated, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 760 mg of a pale yellow solid.

[0765] Compound 028-5:

[0766]

[0767] Compound 028-4 (380 mg, 1.0 mmol) and sodium perborate tetrahydrate (770 mg, 5.0 mmol) were added to 20 mL of acetic acid, and the solution was heated at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, neutralized to alkaline with saturated sodium bicarbonate solution, extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain 410 mg of a pale yellow solid.

[0768] Compound 028-6:

[0769]

[0770] Compound 028-5 (410 mg, 0.97 mmol), intermediate B4 (483 mg, 1.2 mmol), and methanesulfonic acid (576 mg, 6.0 mmol) were added to 8 mL of tert-butanol and reacted overnight at 85 °C. After the reaction was complete, the solution was concentrated, the reaction solution was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 840 mg of brown solid. This solid was not purified and proceeded directly to the next step of the reaction.

[0771] Compound 028-7:

[0772]

[0773] Compound 028-6 (840 mg, crude) was reacted with potassium hydroxide (1.3 g, 23.2 mmol) in 15 mL of methanol and 5 mL of water at 85 °C for 48 hours. After the reaction was complete, the solution was concentrated, and an appropriate amount of water was added to the reaction solution. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 280 mg of a pale yellow solid.

[0774] Compound 028:

[0775]

[0776] Compound 028-7 (200 mg, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.60 mmol), and 1-hydroxybenzotriazole (81 mg, 0.6 mmol) were added to 10 mL of DMF, followed by the dropwise addition of N,N-diisopropylethylamine (155 mg, 1.2 mmol). The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, and an appropriate amount of water was added. The solution was then extracted three times with dichloromethane / methanol (10:1). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was then purified by reverse-phase preparative chromatography to obtain 46 mg of white solid.

[0777] 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.77(s,1H),8.71(s,1H),8.22(s,1H),8.00( s,1H),7.69(d,J=8.0Hz,1H),7.44(s,1H),7.32(d,J=8.0Hz,1H),6.37(s,1H),3.61 (s,1H),3.29-3.21(m,1H),3.07(d,J=12.0Hz,2H),2.65-2.54(m,1H),2.47-2.25(m ,5H),2.21(s,3H),1.84(d,J=8.0Hz,2H),1.67-1.53(m,2H),0.97(d,J=8.0Hz,6H).

[0778] Example 50 Synthesis of target compound 029

[0779]

[0780] Compound 029:

[0781]

[0782] Intermediate C4 (50 mg, 0.123 mmol), intermediate B1 (40 mg, 0.123 mmol), and p-toluenesulfonic acid monohydrate (35 mg, 0.185 mmol) were dissolved in n-butanol (1.2 mL) and stirred at 120 °C for 16 hours. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with acetonitrile to give a white solid compound 029 (20.1 mg, yield 24%). MS m / z (ESI): 690.3 (M+H) + .

[0783] 1H NMR(400MHz, CDCl3)δ8.78(s,1H),8.20-8.16(m,2H),7.89(s,1H),7.34(s,1H),7.22-7.17(m,2H),6.59(s,1H),3.83(s,3H),3.45-3.42(m,2H) ,3.15-3.11(m,2H),3.02-2.98(m,2H),2.68-2.46(m,12H),2.39-2.35( m,1H),2.32(s,3H),2.11(s,3H),1.96-1.93(m,2H),1.75-1.67(m,2H).

[0784] Example 51 Synthesis of target compound 030

[0785]

[0786] Compound 030:

[0787]

[0788] Intermediate C6 (60 mg, 0.17 mmol), intermediate B1 (53 mg, 0.17 mmol), and p-toluenesulfonic acid monohydrate (48 mg, 0.26 mmol) were dissolved in n-butanol (3 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography to obtain a yellow solid hydrochloride compound 030 (24 mg, yield 23%). MS m / z (ESI): 644 (M+H) + .

[0789] 1 H NMR(400MHz,D2O)δ8.15(s,1H),7.42(dd,J=11.2,6.2Hz,2H),7.26(s,1H),6.98(s,1H),3.84–3 .37(m,18H),3.06–3.00(m,5H),2.49–2.41(m,6H),2.23(dd,J=21.5,12.0Hz,2H),2.13(s,3H).

[0790] Example 52 Synthesis of target compound 031

[0791]

[0792] Compound 031-1:

[0793]

[0794] Intermediate A5 (4.0 g, 19.32 mmol) was dissolved in acetic acid (60 mL), and a solution of bromine (3.9 g, 30.91 mmol) in acetic acid (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 3 h. After the reaction was complete, the reaction mixture was quenched with saturated sodium sulfite solution, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, a brown oily compound 031-1 (5.0 g, 91% yield) was obtained. MS m / z (ESI): 286 (M+H) + .

[0795] Compound 031-2:

[0796]

[0797] Compound 031-1 (5.0 g, 17.48 mmol) was dissolved in concentrated hydrochloric acid (50 mL) and stirred at 110 °C for 3 h. After the reaction was complete, the reaction solution was cooled to 0 °C, the pH was adjusted to 9-10 with sodium hydroxide, and the mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give compound 031-2 (3.1 g, 74% yield) as a pale yellow solid. MS m / z (ESI): 244 (M+H) + .

[0798] Compound 031-3:

[0799]

[0800] Compound 031-2 (2.1 g, 8.64 mmol), zinc cyanide (1.5 g, 12.96 mmol), Pd₂(dba)₃ (1.6 g, 1.73 mmol), and X-phos (822 mg, 1.73 mmol) were dissolved in N-methylpyrrolidone (15 mL) and reacted in a microwave-assisted reaction at 150 °C for 50 min. After cooling to room temperature, the mixture was filtered and washed with ethanol to give a yellow solid, compound 031-3 (1.4 g, 85% yield). MS m / z (ESI): 191 (M+H) + .

[0801] Compound 031-4:

[0802]

[0803] Compound 031-3 (240 mg, 1.26 mmol), 2,4,5-trichloropyrimidine (693 mg, 3.79 mmol), and DIEA (213 mg, 1.65 mmol) were dissolved in ethanol (15 mL) and stirred at 80 °C for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethanol to give a white solid, compound 031-4 (110 mg, 26% yield). MS m / z (ESI): 337 (M+H) + .

[0804] Compound 031-5:

[0805]

[0806] Compound 031-4 (110 mg, 0.33 mmol) and sodium perborate tetrahydrate (252 mg, 1.64 mmol) were added to acetic acid (4 mL), and the solution was heated at 60 °C for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, the mixture was extracted three times with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid, compound 031-5 (15 mg, yield 13%). MS m / z (ESI): 369 (M+H) + .

[0807] Compound 031:

[0808]

[0809] Compound 031-5 (15 mg, 0.04 mmol), intermediate B1 (13 mg, 0.04 mmol), and p-toluenesulfonic acid monohydrate (11 mg, 0.06 mmol) were dissolved in n-butanol (0.5 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a yellow solid compound 031 (7 mg, yield 27%). MS m / z (ESI): 651 (M+H) + .

[0810] 1H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 8.67 (d, J = 8.8Hz, 1H), 8.19 (s, 1H), 7.89 (s, 1 H),7.68(d,J=8.8Hz,1H),7.38(s,1H),6.63(s,1H),3.87(s,3H),3.52(dd,J=7.5 ,4.9Hz,2H),3.29(t,J=6.3Hz,2H),3.18(d,J=11.5Hz,2H),3.10–2.47(m,12H),2 .41(m,1H),2.34(s,3H),2.17(s,3H),1.98(d,J=11.6Hz,2H),1.82–1.68(m,2H).

[0811] Example 53 Synthesis of target compound 032

[0812]

[0813] Compound 032:

[0814]

[0815] Intermediate C5 (160 mg, 0.34 mmol), intermediate B1 (109 mg, 0.34 mmol), and p-toluenesulfonic acid (98 mg, 0.52 mmol) were dissolved in 5 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 90.0 mg of a white solid.

[0816] MS m / z (ESI): 750.3 [M+H] + .

[0817] 1H NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.20(s,1H),8.12(d,J=12.0Hz,1H),7.88( s,1H),7.67(d,J=12.0Hz,1H),7.35(s,1H),6.60(s,1H),3.83(s,3H),3.46-3.40 (m,2H),3.14(d,J=8.0Hz,2H),3.05(t,J=8.0Hz,2H),2.83-2.43(m,12H),2.41-2 .35(m,1H),2.32(s,3H),2.12(s,3H),1.95(d,J=12.0Hz,2H),1.79-1.65(m,2H).

[0818] Example 54 Synthesis of target compound 033

[0819]

[0820] Compound 033:

[0821]

[0822] Intermediate C7 (120 mg, 0.28 mmol), intermediate B1 (89 mg, 0.28 mmol), and p-toluenesulfonic acid (80 mg, 0.42 mmol) were dissolved in 5 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 80.0 mg of a white solid. MS m / z (ESI): 706.3 [M+H] + .

[0823] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.21 (d, J = 8.0Hz, 1H), 8.14 (s, 1H), 7.92 (s ,1H),7.70(d,J=12.0Hz,1H),7.37(s,1H),6.62(s,1H),3.86(s,3H),3.48-3.41( m,2H),3.17(d,J=12.0Hz,2H),3.08(t,J=4.0Hz,2H),2.80-2.45(m,12H),2.44-2 .38(m,1H),2.35(s,3H),2.16(s,3H),1.97(d,J=12.0Hz,2H),1.82-1.67(m,2H).

[0824] Example 55 Synthesis of target compound 034

[0825]

[0826] Compound 034:

[0827]

[0828] Intermediate C8 (119 mg, 0.28 mmol), intermediate B1 (89 mg, 0.28 mmol), and p-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) were dissolved in n-butanol (3 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a yellow solid compound 034 (100 mg, yield 51%). MS m / z (ESI): 704 (M+H) + .

[0829] 1 H NMR(400MHz, CDCl3)δ9.13(s,1H),8.35(s,1H),8.23(s,1H),7.90(s,1H), 7.35(s,1H),6.96(s,1H),6.60(s,1H),3.86(s,3H),3.53–3.39(m,2H),3.1 7(d,J=11.5Hz,2H),3.05(t,J=6.2Hz,2H),2.59(m,12H),2.37(m,1H),2.34 (s,3H),2.13(s,3H),1.95(d,J=11.6Hz,2H),1.71(dt,J=11.9,8.8Hz,2H).

[0830] Example 56 Synthesis of target compound 035

[0831]

[0832] Compound 035:

[0833]

[0834] Intermediate C9 (200 mg, 0.53 mmol), intermediate B1 (168 mg, 0.53 mmol), and p-toluenesulfonic acid monohydrate (150 mg, 0.79 mmol) were dissolved in n-butanol (6 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a yellow solid compound 035 (50 mg, yield 14%). MS m / z (ESI): 662 (M+H) + .

[0835] 1 H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.41 (d, J = 1.6Hz, 1H), 8.14 (s, 1H), 7.90 (s, 1H) ),7.34(s,1H),6.95(s,1H),6.61(s,1H),3.86(s,3H),3.44(dd,J=7.6,5.0Hz,2H ),3.15(d,J=11.8Hz,2H),3.03(t,J=6.3Hz,2H),2.96–2.43(m,12H),2.37(m,1H) ,2.34(s,3H),2.14(s,3H),1.95(d,J=11.1Hz,2H),1.71(dt,J=11.9,8.8Hz,2H).

[0836] Example 57 Synthesis of target compound 036

[0837]

[0838] Compound 036-1:

[0839]

[0840] Compound B2-4 (500 mg, 1.34 mmol) was dissolved in 26 mL of methanol, and 100 mg of palladium on carbon was added. The mixture was purged twice with hydrogen gas, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the solution was filtered, concentrated, and purified by column chromatography (dichloromethane:methanol = 20:1) to give 185 mg of a light red solid.

[0841] Compound 036:

[0842]

[0843] Intermediate C3 (130 mg, 0.37 mmol), compound 036-1 (144 mg, 0.37 mmol), and p-toluenesulfonic acid monohydrate (107 mg, 0.56 mmol) were dissolved in 5 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 60.0 mg of a white solid. MS m / z (ESI): 698.6 [M+H] + .

[0844] 1 H NMR(400MHz,D2O)δ8.17(s,1H),7.42-7.23(m,4H),6.96(s,1H),3.95-3.42(m,18H),3.05-2.9 4(m,5H),2.43(d,J=12.0Hz,2H),2.37-2.20(m,6H),1.17-1.04(m,2H),0.07(t,J=8.0Hz,3H).

[0845] Example 58 Synthesis of target compound 037

[0846]

[0847] Compound 037:

[0848]

[0849] Intermediate C3 (70 mg, 0.18 mmol), intermediate B6 (60 mg, 0.18 mmol), and p-toluenesulfonic acid monohydrate (52 mg, 0.27 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 20.0 mg of a white solid. MS m / z (ESI): 686.4 [M+H] + .

[0850] 1 H NMR(400MHz,D2O)δ8.17(s,1H),7.42-7.23(m,4H),6.96(s,1H),3.89-3.35(m,18H), 3.05-2.94(m,5H),2.43(d,J=12.0Hz,2H),2.37-2.20(m,6H),0.83(t,J=4.0Hz,3H).

[0851] Example 59 Synthesis of target compound 038

[0852]

[0853] Compound 038:

[0854]

[0855] Intermediate C4 (60 mg, 0.147 mmol), intermediate B6 (49 mg, 0.147 mmol), and p-toluenesulfonic acid monohydrate (42 mg, 0.221 mmol) were dissolved in n-butanol (1.5 mL) and stirred at 120 °C for 16 hours. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative reversed-phase chromatography to give a white solid compound 038 (53.5 mg, yield 45%). MS m / z (ESI): 704.4 [M+H] + .

[0856] 1 H NMR(400MHz,D2O)δ8.25(s,1H),7.39(s,1H),7.37(s,2H),7.04(s,1H),3.85-3.71(m,9H),3 .65-3.51(m,9H),3.06(s,3H),3.03-3.00(m,2H),2.51-2.27(m,8H),0.97(t,J=7.2Hz,3H).

[0857] Example 60 Synthesis of target compound 039

[0858]

[0859] Compound 039:

[0860]

[0861] Intermediate C5 (70 mg, 0.15 mmol), intermediate B6 (50 mg, 0.15 mmol), and p-toluenesulfonic acid monohydrate (43 mg, 0.23 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 25.0 mg of a white solid. MS m / z (ESI): 764.4 [M+H] + .

[0862] 1 H NMR(400MHz,D2O)δ8.12(s,1H),7.62(d,J=12.0Hz,1H),7.19(s,1H),7.12(d,J=8.0Hz,1H),3.70(s,3H ),3.65-3.05(m,15H),2.98-2.85(m,5H),2.37-2.18(m,6H),2.11-1.91(m,2H),0.81(t,J=8.0Hz,3H).

[0863] Example 61 Synthesis of target compound 040

[0864]

[0865] Compound 040:

[0866]

[0867] Intermediate C6 (46 mg, 0.13 mmol), intermediate B6 (42 mg, 0.13 mmol), and p-toluenesulfonic acid monohydrate (36 mg, 0.19 mmol) were dissolved in n-butanol (3 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and then extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography to obtain a yellow solid hydrochloride compound 040 (30 mg, yield 36%). MS m / z (ESI): 658 (M+H) + .

[0868] 1 H NMR(400MHz,D2O)δ8.12(s,1H),7.36(dd,J=11.2,6.2Hz,2H),7.32(s,1H),6.96(s,1H),3.81-3.56( m,18H),3.02-2.97(m,5H),2.42-2.40(m,6H),2.22(dd,J=20.9,11.8Hz,2H),0.95(t,J=7.4Hz,3H).

[0869] Example 62 Synthesis of target compound 041

[0870]

[0871] Compound 041:

[0872]

[0873] Intermediate C7 (60 mg, 0.14 mmol), intermediate B6 (47 mg, 0.15 mmol), and p-toluenesulfonic acid monohydrate (41 mg, 0.21 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 23.0 mg of a white solid. MS m / z (ESI): 720.4 [M+H] + .

[0874] 1 H NMR(400MHz,D2O)δ8.05(s,1H),7.67(d,J=8.0Hz,1H),7.25-7.17(m,1H),7.13(d,J=8.0Hz,1H),6.88-6.79(m,1H) ,3.70(s,3H),3.65-3.10(m,15H),3.01-2.84(m,5H),2.40-2.20(m,6H),2.20-1.96(m,2H),0.82(t,J=8.0Hz,3H).

[0875] Example 63 Synthesis of target compound 042

[0876]

[0877] Compound 042:

[0878]

[0879] Intermediate C8 (60 mg, 0.14 mmol), intermediate B6 (47 mg, 0.14 mmol), and p-toluenesulfonic acid monohydrate (41 mg, 0.21 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 21.0 mg of a white solid. MS m / z (ESI): 718.4 [M+H] + .

[0880] 1H NMR(400MHz,D2O)δ8.12(s,1H),7.33(s,1H),7.27(s,1H),7.22(s,1H),6.86(s,1H),3.70(s,3H),3.65-3.33(m ,12H),3.26(t,J=12.0Hz,3H),2.97-2.86(m,5H),2.41-2.19(m,6H),2.15-1.99(m,2H),0.82(t,J=8.0Hz,3H).

[0881] Example 64 Synthesis of target compound 043

[0882]

[0883] Compound 043:

[0884]

[0885] Intermediate C9 (60 mg, 0.16 mmol), intermediate B6 (53 mg, 0.16 mmol), and p-toluenesulfonic acid (46 mg, 0.24 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 23.0 mg of a white solid. MS m / z (ESI): 674.6 [M+H] + .

[0886] 1 H NMR(400MHz,D2O)δ8.15(s,1H),7.43(s,1H),7.39(s,1H),7.37(s,1H),7.07(s,1H),3.70(s,3H),3 .65-3.25(m,15H),3.05-2.96(m,5H),2.41-2.19(m,6H),2.15-1.99(m,2H),0.90(t,J=8.0Hz,3H).

[0887] Example 65 Synthesis of target compound 044

[0888]

[0889] Compound 044:

[0890]

[0891] Intermediate C8 (60 mg, 0.14 mmol), intermediate B5 (37 mg, 0.14 mmol), and p-toluenesulfonic acid monohydrate (41 mg, 0.21 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated at 120 °C overnight. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 25.0 mg of a white solid. MS m / z (ESI): 649.4 [M+H] + .

[0892] 1 H NMR(400MHz,D2O)δ8.21-8.18(m,1H),7.47(s,1H),7.35-7.31(m,1H),7.04(s,1H), 3.80(s,3H),3.74-3.54(m,7H),3.02-2.85(m,8H),2.45-2.33(m,6H),2.11(s,3H).

[0893] Example 66 Synthesis of target compound 045

[0894]

[0895] Compound 045-1:

[0896]

[0897] Compound B6-2 (1.5 g, 6.00 mmol), 4-dimethylaminopiperidine (806 mg, 6.30 mmol), and potassium carbonate (1.1 g, 7.80 mmol) were dissolved in DMF (20 mL) and stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow oily compound 045-1 (1.4 g, 65% yield). MS m / z (ESI): 358 (M+H) + .

[0898] Compound 045-2:

[0899]

[0900] Compound 045-1 (1.4 g, 3.91 mmol), tributylvinyltin (2.5 g, 7.82 mmol), bis(triphenylphosphine)palladium dichloride (274 mg, 0.39 mmol), cuprous bromide (168 mg, 1.17 mmol), and triphenylphosphine (307 mg, 1.17 mmol) were dissolved in toluene (30 mL) and stirred overnight at 110 °C under nitrogen protection. After the reaction was complete, the solvent was removed under reduced pressure, the residue was diluted with dichloromethane, extracted with saturated potassium fluoride solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give a yellow oily compound 045-2 (1.1 g, 92% yield). MS m / z (ESI): 306 (M+H) + .

[0901] Compound 045-3:

[0902]

[0903] Compound 045-2 (1.1 g, 3.61 mmol) was dissolved in methanol (60 mL), and 10% wet palladium on carbon (200 mg) was added at room temperature. The reaction system was purged three times with hydrogen and stirred overnight at room temperature under normal pressure. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to give a brown oily compound 045-3 (900 mg, 90% yield), which was used directly in the next reaction. MS m / z (ESI): 278 (M+H) + .

[0904] Compound 045:

[0905]

[0906] Compound 045-3 (33 mg, 0.12 mmol), intermediate C8 (50 mg, 0.12 mmol), and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) were dissolved in n-butanol (2 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography to give a yellow solid hydrochloride compound 045 (25 mg, yield 32%). MS m / z (ESI): 663 (M+H) + .

[0907] 1H NMR(400MHz,D2O)δ8.25(s,1H),7.40(d,J=10.8Hz,3H),7.10(s,1H),3.82(s,3H),3.79–3.70(m,5H),3. 57(dd,J=7.4,4.4Hz,2H),3.00(d,J=5.5Hz,2H),2.93(s,6H),2.51–2.21(m,8H),0.89(t,J=7.2Hz,3H).

[0908] Example 67 Synthesis of target compound 046

[0909]

[0910] Compound 046:

[0911]

[0912] Intermediate (60 mg, 0.14 mmol), 2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperazinyl]-aniline (43.2 mg, 0.14 mmol) (synthesized as with intermediate B1, starting from m-fluorophenol), and p-toluenesulfonic acid (41 mg, 0.21 mmol) were dissolved in 3 mL of n-butanol. The reaction mixture was heated overnight at 120 °C. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and the pH was adjusted to 10–11 by adding saturated sodium carbonate aqueous solution. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed three times with saturated brine. The mixture was dried, concentrated, and purified by reversed-phase column chromatography to obtain 25.0 mg of a white solid. MS m / z (ESI): 692.3 [M+H] +

[0913] 1 H NMR(400MHz,D2O)δ8.15-7.99(m,1H),7.42(s,1H),7.31(d,J=4.0Hz,1H),7.25-7.08(m,1H),6.96(s,1H),6.83(d,J=8 .0Hz,1H),3.72(s,3H),3.65-3.20(m,15H),2.94(s,3H),2.90-2.76(m,2H),2.43(d,J=12.0Hz,2H)2.27-1.95(m,4H).

[0914] Example 68 Synthesis of target compound 047

[0915]

[0916] Compound 047-2:

[0917]

[0918] Compound 047-1 (1.0 g, 4.86 mmol), 1-methyl-4-(4-piperidinyl)piperazine (936 mg, 5.11 mmol), and potassium carbonate (872 mg, 6.32 mmol) were dissolved in DMF (20 mL) and stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was diluted in water, extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid, compound 047-2 (1.8 g, 100% yield). MS m / z (ESI): 369 (M+H) + .

[0919] Compound 047-3:

[0920]

[0921] Compound 047-2 (1.8 g, 4.86 mmol), iron powder (1.4 g, 24.30 mmol), and ammonium chloride (2.6 g, 48.60 mmol) were added to ethanol (5 mL) and water (15 mL), and stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the reaction solution was filtered, the filtrate was concentrated, and purified by column chromatography to give a gray solid compound 047-3 (1.2 g, yield 73%). MS m / z (ESI): 339 (M+H) + .

[0922] Compound 047:

[0923]

[0924] Compound 047-3 (40 mg, 0.12 mmol), intermediate C8 (50 mg, 0.12 mmol), and p-toluenesulfonic acid monohydrate (34 mg, 0.18 mmol) were dissolved in n-butanol (2 mL) and stirred overnight at 120 °C. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reversed-phase column chromatography to give a yellow solid hydrochloride compound 047 (16 mg, yield 19%). MS m / z (ESI): 724 (M+H) + .

[0925] 1H NMR(400MHz,D2O)δ8.19(s,1H),7.27(d,J=17.9Hz,3H),6.76(s,1H),4.00–3.49(m,18 H),3.05(s,3H),2.96–2.84(m,4H),2.35–2.28(m,4H),1.99(dd,J=20.2,10.8Hz,2H).

[0926] Example 69 Synthesis of target compound 048

[0927]

[0928] Compound 048-2:

[0929]

[0930] Compound 048-1 (2.5 g, 14.27 mmol) was dissolved in 60 mL of DMF, and then potassium carbonate (5.92 g, 42.82 mmol) was added. Iodomethane (3.04 g, 28.56 mmol) was slowly added dropwise to the reaction mixture at room temperature, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was concentrated, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid 048-2 (2.11 g, yield: 78%).

[0931] 1 H NMR (400MHz, DMSO-d6) δ8.26-8.21(m,1H),7.66-7.61(m,1H),3.93(s,3H).

[0932] Compound 048-3:

[0933]

[0934] 048-2 (1.0 g, 5.3 mmol) and 1-methyl-4-(piperidin-4-yl)piperazine (1.068 g, 5.8 mmol) were added to 6 mL of DMSO and reacted at 90 °C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature, 60 mL of saturated sodium bicarbonate aqueous solution was added, and the mixture was stirred for 10 minutes. The solid was filtered and dried to give a yellow solid 048-3 (1.75 g, yield: 94%). MS m / z (ESI): 353.2 [M+H] + .

[0935] Compound 048-4:

[0936]

[0937] Compound 048-3 (1.0 g, 2.84 mmol) was dissolved in methanol (100 mL), and then 10% wetted palladium on carbon (450 mg) was added. The reaction mixture was stirred under hydrogen atmosphere at atmospheric pressure for 2 hours. The reaction mixture was filtered and concentrated to give a brown oily compound 048-4 (960 mg, 98% yield). MS m / z (ESI): 323.3 [M+H] + .

[0938] Compound 048:

[0939]

[0940] Intermediate C8 (200 mg, 0.473 mmol), 048-4 (168 mg, 0.52 mmol), and p-toluenesulfonic acid monohydrate (135 mg, 0.71 mmol) were dissolved in n-butanol (5 mL) and stirred at 120 °C for 16 hours. After the reaction was complete, the solution was concentrated, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was slurried with acetonitrile to give a white solid compound 048 (130 mg, yield 38%). MS m / z (ESI): 710.2 [M+H] + .

[0941] 1 H NMR (400MHz, CDCl3) δ9.04(s,1H),8.24-8.22(m,2H),7.95(d,J=14.0Hz,1H),7.45(s,1H),7.01(s,1H),6.52(d,J=7.6Hz,1H ),3.85(s,3H),3.46-3.43(m,4H),3.04-3.01(m,2H),2.69-2.56(m,6H),2.51-2.37(m,7H),2.32(s,3H),1.94-1.74(s,4H).

[0942] Effect of Compound 1 on EGFR Enzyme Activity

[0943] Experimental methods:

[0944] Dissolve the test compound in 100% DMSO to prepare a 10 mM stock solution. Dilute the compound 5-fold with DMSO in the first well of a 96-well plate, and then perform 4-fold serial dilutions in a 96-well dilution plate. Add 1 μL of the serially diluted compound to 39 μL of kinase buffer and shake on a microplate shaker for 20 min.

[0945] (1) Prepare 2.5×EGFR (0.2 nM) using 1× enzyme reaction buffer. Add 2 μL of kinase and 1 μL of the compound at different concentrations to each well of a 384 reaction plate. Seal the 384 reaction plate with sealing film, centrifuge at 1000g for 1 minute, and incubate at room temperature for 10 minutes.

[0946] (2) Prepare 2.5×TK-substrate-biotin (2.5μM) and 2.5×ATP (EGFR, 5μM) with 1× enzyme reaction buffer, mix well, and add 2μL of TK-substrate-biotin / ATP mixture to a 384 reaction plate.

[0947] (3) Seal the 384 reaction plate with sealing film, centrifuge at 1000g for 30 seconds, react at 22℃ for 40 minutes, and the final concentrations of the test compounds in the test system are 10000nM, 2500nM, 625nM, 156.3nM, 39.1nM, 9.8nM, 2.4nM, 0.61nM, 0.153nM and 0.038nM.

[0948] (4) Prepare 2×Sa-XL 665 (125nM) and 1×TK-antibady-Cryptate using HTRF detection buffer.

[0949] Add 5 μL of a mixture of Sa-XL 665 and TK-antibody-Cryptate to each well, centrifuge at 1000g for 30 seconds, and react at room temperature for 1 hour.

[0950] (5) Use a BioTek microplate reader to read the fluorescence signals of TK-antibody-Cryptate at 620 nm and Sa-XL 665 at 665 nm, and calculate the ratio R of the fluorescence signals in each well.

[0951]

[0952] Wherein, the ratio R represents the degree of kinase activity; AU represents the intensity of the fluorescence signal.

[0953] (6) The IC50 of the compound was obtained by curve fitting based on the R value at different concentrations. 50 .

[0954] For the synthesis of compound 000, refer to compound 85 (i.e., TQB3804) in WO2020 / 216371. TQB3804: Osimertinib

[0955] Table 1. Inhibitory activity of target and comparative compounds against kinases.

[0956]

[0957]

[0958] Effects Example 2: Effects of the target compound on the proliferation of EGFR mutant cell lines and A431 cell lines

[0959] Cell culture steps:

[0960] Baf3-EGFR L858R T790M C797S cells, Baf3-EGFR L858R T790M cells, and Baf3-EGFRd746-750 T790M C797S cells were cultured in 1640 medium with 1% penicillin-streptomycin mixture, 10% FBS, 1% Glumax and 2 μg / mL Puromycin added, and cultured at 37℃ and 5% CO2.

[0961] A431 cells were cultured in DMEM medium with 1% penicillin-streptomycin mixture, 10% FBS, and 1% Glumax added, and cultured at 37°C and 5% CO2.

[0962] Compound preparation

[0963]

[0964] The target compound and control compound were diluted 3-fold to 10 concentrations starting from a 10 mM stock solution.

[0965] The blank control wells were prepared by adding 0.1% DMSO to the cells and served as high-reading control wells.

[0966] The positive control compound at its highest concentration was added to the cells to serve as a low-reading control well.

[0967] Transfer 30 nL of serially diluted compound to a 384 cell culture plate using an Echo 665 and centrifuge at 1000 rpm for 30 s.

[0968] Cell plating steps:

[0969] Cells are cultured routinely until the cell density reaches 80%-90%, and when the required number is reached, the cells are harvested.

[0970] Resuspend the cells in the corresponding culture medium, count them, and prepare suspensions of Baf3-EGFR L858R T790M C797S cells, Baf3-EGFR L858R T790M cells, Baf3-EGFR d746-750 T790M C797S cells, and A431 cells.

[0971] Add the cell suspension to each well of a 384-well plate, with 30 μL of Baf3-EGFR L858R T790M C797S cells, Baf3-EGFR L858R T790M cells, and Baf3-EGFR d746-750 T790M C797S cells per well, and 800 A431 cells per well.

[0972] Final concentrations of the target compounds: 1000 nM, 333.33 nM, 111.11 nM, 37.04 nM, 12.35 nM, 4.12 nM, 1.37 nM, 0.46 nM, 0.15 nM, 0.05 nM. Incubated at 37°C in a 5% CO2 incubator for 72 hours.

[0973] CTG method detection steps:

[0974] Add 30 μL of CTG reagent (Celltiter Glo kit) to each well, place on a shaker and shake for 2 minutes, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature in the dark for 30 minutes.

[0975] The chemiluminescence signal value was read using an Envision instrument.

[0976] Substitute the chemiluminescence signal value into the following formula

[0977]

[0978] The inhibition rate Y was calculated.

[0979] Data Analysis

[0980] Using GraphPad Prism 8 software, substitute the calculated Y value into the following nonlinear fitting formula:

[0981]

[0982] To calculate IC 50 (Half-maximal inhibitory concentration).

[0983] Where X is the log value of the compound concentration, Bottom is the minimum value obtained by fitting the experimental curve, Top is the maximum value obtained by fitting the experimental curve, and Hillslope is the slope of the experimental curve.

[0984] The compound of TQB3804 is compound 000.

[0985] Table 2. Effects of the target compound on the proliferation of EGFR mutant and A431 cell lines.

[0986]

[0987]

[0988] As can be seen from Examples 1 and 2 above, the target compounds 1 to 48 of the present invention have good inhibitory activity against the C797S drug resistance mutation in the EGFR gene.

Claims

1. A compound of general formula (Ib), or its racemic mixture, isotopic label, or pharmaceutically acceptable salt thereof, General formula (Ⅰb) in, When A is S, m = 0 or 2, n = 1; When A is P, m=1, n=2; Y is either N or CH; Each of R2, R4, and R5 is independently H, halogen, OH, NH2, C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 alkoxy. R1 and R3 are linked together to form -NR 11 -or-C(O)NR 11 -; Alternatively, R4 and R5 can be linked together to form unsubstituted or substituted C1-C4 alkane chains or C2-C4 alkene chains; R N1 R Y1 R Y2 Independently H, halogen, OH, C1-C6 alkyl or (R N2 )2N-;R N2 Independently H, halogen, OH, C1-C6 alkyl, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked by 1 to 10 R's; Or R N1 and R Y1 They covalently form C1-C4 alkyl chains with 1-3 R's; Each R' is independently H, halogen, OH, or C1-C6 alkyl; Among them, R 11 Independently, it is H or a C1-C6 alkyl group; R'' can be a halogen, OH, or a C1-C6 alkyl group.

2. The compound according to claim 1, characterized in that, When R1 and R3 are linked together to form NR 11 hour, Then general formula (Ⅰb) takes the form of general formula (Ⅰl). General formula (Ⅰl).

3. The compound according to claim 1, characterized in that, When R1 and R3 are linked together to form -C(O)NR 11 -hour, Then the general formula (Ⅰb) takes the form of the following general formula (Ⅰm). General formula (Ⅰm).

4. The compound according to claim 2, characterized in that, When R N1 and R Y1 Together they form a C2 alkyl chain with two R's. Then the general formula (Ⅰl) takes the form of the following general formula (Ⅰn). General formula (Ⅰn).

5. The compound according to claim 3, characterized in that, When R N1 and R Y1 Together they form a C2 alkyl chain with two R's. The general formula (Ⅰm) then takes the form of the general formula (Ⅰo). General formula (Ⅰo).

6. The compound according to claim 4, characterized in that, When Y is CH, R Y2 For (R) N2 When 2N-, Then the general formula (Ⅰn) takes the form of the following general formula (Ⅰp). General formula (Ⅰp).

7. The compound according to claim 5, characterized in that, When Y is CH, R Y2 For (R) N2 When 2N-, Then the general formula (Ⅰo) takes the form of the following general formula (Ⅰq). General formula (Ⅰq).

8. The compound according to claim 6, characterized in that, When two R N2 Together with N, it forms a six-membered heteroalkyl ring with five R' atoms and two N atoms. Then the general formula (Ⅰp) takes the form of the following general formula (Ⅰr). General formula (Ⅰr).

9. The compound according to claim 7, characterized in that, When two R N2 Together with N, it forms a six-membered heteroalkyl ring with five R' atoms and two N atoms. Then the general formula (Ⅰq) takes the form of the following general formula (Ⅰs). General formula (Ⅰs).

10. The compound according to any one of claims 1 to 9, characterized in that, Each R2 is independently H, halogen, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, or C1-C4 alkoxy.

11. The compound according to claim 10, characterized in that, Each R2 is independently H, halogen, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, or C1-C3 alkoxy.

12. The compound according to any one of claims 1 to 9, characterized in that, R4 is H, halogen, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl or C1-C4 alkoxy; Alternatively, R4 and R5 can be linked together to form unsubstituted C1-C4 alkane chains or C2-C4 alkene chains, or chains substituted with 1-2 R''.

13. The compound according to claim 12, characterized in that, R4 is H, halogen, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl or C1-C3 alkoxy; Alternatively, R4 and R5 can be linked together to form an unsubstituted or substituted C2-C3 alkyl chain.

14. The compound according to any one of claims 1 to 9, characterized in that, R5 can be H, halogen, OH, NH2, C1-C4 alkyl, C2-C4 alkenyl, or C1-C4 alkoxy.

15. The compound according to claim 14, characterized in that, R5 can be H, halogen, OH, NH2, C1-C3 alkyl, C2-C3 alkenyl, or C1-C3 alkoxy.

16. The compound according to any one of claims 1 to 9, characterized in that, R4 and R5 are linked together to form unsubstituted C1-C4 alkane chains or C2-C4 alkene chains, or chains substituted with 1-2 R''.

17. The compound of claim 16, characterized in that, R4 and R5 are linked together to form an unsubstituted or substituted C2-C3 alkyl chain.

18. The compound according to any one of claims 1 to 3, characterized in that, R N1 R Y1 R Y2 Independently, it is H, halogen, OH, C1-C4 alkyl or (R N2 )2N-;R N2 Independently H, halogen, OH, C1-C4 alkyl, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked by 1 to 6 R's; Or R N1 and R Y1 They covalently form C1-C3 alkyl chains with 1-2 R's.

19. The compound of claim 18, characterized in that, R N1 R Y1 R Y2 Independently, it is H, halogen, OH, C1-C3 alkyl or (R N2 )2N-;R N2 Independently H, halogen, OH, C1-C3 alkyl, or (R N2 )2N- is a 6-membered heteroalkyl ring group with 2 to 5 R' links and 2 N atoms; Or R N1 and R Y1 They covalently form C1-C2 alkyl chains with 1-2 R's.

20. The compound according to claim 4 or 5, characterized in that, R Y2 Independently, it is H, halogen, OH, C1-C4 alkyl or (R N2 )2N-;R N2 Independently H, halogen, OH, C1-C4 alkyl, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked by 1 to 6 R's.

21. The compound according to claim 20, characterized in that, R Y2 Independently, it is H, halogen, OH, C1-C3 alkyl or (R N2 )2N-;R N2 Independently H, halogen, OH, C1-C3 alkyl, or (R N2 )2N- is a 6-membered heteroalkyl ring group with 2 to 5 R's linked together and containing 2 N atoms.

22. The compound according to claim 6 or 7, characterized in that, R N2 Independently H, halogen, OH, C1-C4 alkyl, or (R N2 )2N- is a 5- to 7-membered heteroalkyl ring group with 1 to 3 N atoms linked by 1 to 6 R's.

23. The compound according to claim 22, characterized in that, R N2 Independently H, halogen, OH, C1-C3 alkyl, or (R N2 )2N- is a 6-membered heteroalkyl ring group with 2 to 5 R's linked together and containing 2 N atoms.

24. The compound according to any one of claims 1 to 9, characterized in that, Each R' is independently H, halogen, OH, or C1-C4 alkyl; R 11 Independently, it is H or C1-C4 alkyl; R'' can be independently a halogen, OH, or a C1-C4 alkyl group.

25. The compound according to claim 24, characterized in that, Each R' is independently H, halogen, OH, or C1-C3 alkyl; R 11 Independently, it is H or a C1-C3 alkyl group; R'' can be a halogen, OH, or a C1-C3 alkyl group.

26. The compound according to claim 1, characterized in that, The compound is 。 27. Use of the compound of claim 1 in the preparation of a medicament for treating lung cancer.

28. Use of the compound of claim 1 in the preparation of a medicament for inhibiting EGFR.

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