Compounds as NMT inhibitors and their use

Abstract

The present invention provides a compound having N-myristoyl transferase (NMT) inhibitor activity or a pharmaceutically acceptable salt thereof and a preparation method thereof. The present invention also relates to the use of such compounds as N-myristoyl transferase (NMT) inhibitors for preparing a medicament for treating or preventing infectious diseases or hyperproliferative diseases, wherein infectious diseases include protozoan infections (such as malaria and leishmaniasis) and viral infections (such as human rhinovirus and HIV), and hyperproliferative diseases include lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer, colorectal cancer, etc.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a compound used as an NMT inhibitor and use of the compound or pharmaceutical composition in preparing a drug. Background Art

[0002] In eukaryotic cells, N-myristoylation of proteins is a co-translational and post-translational modification catalyzed by N-myristoyltransferase (NMT). Higher organisms such as humans have two NMT proteins (NMT1 and NMT2), both of which are expressed in most tissues. Typical substrates of NMT include tyrosine kinases pp60c-src and pp60c-yes, BID, and its potential substrates are extensive. Currently, more than 100 myristoylated proteins have been found, distributed in different locations of cells, with different biological functions, mainly involved in important biological processes such as secondary signal transduction, vesicle transport, virus maturation and tumor formation (overexpression in tumor cells). NMT can be involved in the occurrence and development of many diseases, such as cancer, epilepsy, Alzheimer's disease, Noonan-like syndrome, and viral and bacterial infections.

[0003] Rhinovirus (RV) is the main pathogen causing the common cold and is also the cause of diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, but there is currently no targeted treatment. Ed Tate et al. found that after rhinovirus infects the host, the host's ribosome will translate its RNA genome into polyproteins. During the translation, the host's N-myristoylation transferase NMT generates myristoylation modification at the N-terminus of the protein to form a capsid protein precursor. Subsequently, the rhinovirus protease cuts the polyprotein into three parts: VP0, VP3, and VP1, which are then assembled into protomers. Five protomers assemble into a pentamer complex, and finally 12 pentamers and the RNA genome are assembled together to form an infectious virus. Previous mutation experiments have shown that myristoylation modification on VP0 is critical for the assembly of viral capsid proteins, so inhibiting NMT can prevent rhinovirus infection and self-replication. Because this viral mechanism is common, it can inhibit a variety of small RNA virus members including rhinovirus, polio virus, foot-and-mouth disease virus, and hepatitis A virus.

[0004] According to public information, IMP INNOVATIONS LTD has applied for relevant invention patents for NMT inhibitors (WO2017001812), which are mainly used for rhinovirus and HIV infection, malaria and other diseases. In addition, companies such as STEPHEN, ADIR, SEARLE&CO have also obtained relevant patent approvals for NMT inhibitors and their uses (WO2010026365; US5266576; US5942600). In recent years, companies such as VASTCON INC and SHRIVASTAV ANURAAG have also applied for relevant patents for the use of NMT in tumors (WO2017190241; WO2014082178). Based on these studies and findings, it is shown that inhibiting NMT can provide benefits in the treatment of a variety of small RNA viruses and tumors.

[0005] Although some small molecules of NMT inhibitors have been disclosed, there is still a need to develop new compounds with better efficacy and pharmacokinetic results. After continuous exploration, the present invention designs compounds having a structure shown in general formula (I), and finds that compounds having such a structure exhibit excellent effects and functions. Summary of the invention

[0006] The present invention aims to provide a compound or a pharmaceutically acceptable salt thereof as an N-myristoyl transferase inhibitor, which can be used to prepare a medicament for treating or preventing infectious diseases or hyperproliferative diseases, including protozoan infections such as malaria and leishmaniasis, viral infections such as human rhinovirus and HIV, hyperproliferative disorders such as lymphoma (specifically B-cell lymphoma), leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer and colorectal cancer.

[0007] Specifically, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] in,

[0010] W is selected from -O- or -NH-;

[0011] Y 1 Selected from -(CH2) r -, wherein r is selected from 1, 2, 3, 4 or 5;

[0012] Y 2 Does not exist or is wherein q is selected from 1, 2, 3 or 4;

[0013] R 1 Independently selected from -F, -Cl, -Br, -CN, -OR5 、-NR 5 R 6 、-NO2、-N3、C 1-6 Alkyl, -COOR 5 or-CONR 5 R 6 , R 5 and R 6 Each independently selected from H, C 1-6 alkyl;

[0014] n is 0, 1, 2 or 3;

[0015] A is heteroaryl;

[0016] R 4 Independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SR 7 、-(CH2) m C(O)R 7 、-(CH2) m NR 7 R 8 、-(CH2) m S(O)R 7 、-(CH2) m S(O)2R 7 、-(CH2) m OC(O)R 7 、-(CH2) m C(O)OR 7 、-(CH2) m OS(O)2R 7 、-(CH2) m S(O)2OR 7 、-(CH2) m C(O)NR 7 R 8 、-(CH2) m S(O)2NR 7 R 8 、-(CH2) m NR 7 C(O)R 8 、-(CH2) m NR 7 S(O)2R 8 、-(CH2) m NHC(=NH)NR 7 R 8 、-(CH2) m NHC(O)NR 7 R 8 , unsubstituted or s R 9Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy,

[0017] m = 0, 1, 2, 3, 4;

[0018] s = 0, 1, 2, 3, 4, 5 or 6;

[0019] R 7 and R 8 Each independently selected from -H, -NH2, -OH, -COOH, unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy, unsubstituted or s R 10 substituted aryl, unsubstituted or s R 10 substituted heteroaryl, unsubstituted or s R 10 substituted carbocyclic group, unsubstituted or s R 10 substituted heterocyclic group;

[0020] or R 7 and R 8 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;

[0021] Each R 9 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SH, -NH2, -C≡CH, -COOH or C 1-6 Alkoxy;

[0022] Each R 10 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SH, -NH2, -C≡CH, unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy;

[0023] p is 0, 1, 2, 3 or 4;

[0024] Z 1 , Z 2 is C or N, and when C is replaced by H or R 1 replace;

[0025] Z 3 , Z 4 is CH or N;

[0026] Z 6 C or N;

[0027] Z 5 Selected from S or O;

[0028] L=-(CH2) w -, wherein one or more H may be replaced by D;

[0029] w = 0, 1, 2, 3, 4;

[0030] R 2 Selected from -C(O)R 11 、-NR 11 R 12 、-S(O)R 11 、-S(O)2R 11 、-OC(O)R 11 、-C(O)OR 11 、-OS(O)2R 11 、-S(O)2OR 11 、-NR 11 C(O)R 12 、-NR 11 S(O)2R 12 、-C(O)NR 11 R 12 、-S(O)2NR 11 R 12 , unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, -R 14 ;

[0031] t = 0, 1, 2, 3, 4, 5 or 6;

[0032] R 11 and R 12 Each R is independently selected from -H, -NH2, -OH, -CN, unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, unsubstituted or t R 15 substituted aryl, unsubstituted or t R 15 substituted heteroaryl, unsubstituted or t R 15 substituted carbocyclic group, unsubstituted or t R 15 substituted heterocyclic group;

[0033] or R 11 and R12 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;

[0034] Each R 13 Each independently selected from -D, -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH or C 1-6 Alkoxy;

[0035] R 14 Selected from unsubstituted or t R 15 substituted aryl, unsubstituted or t R 15 substituted heteroaryl, unsubstituted or t R 15 substituted carbocyclic group, unsubstituted or t R 15 substituted heterocyclic group;

[0036] Each R 15 Each R is independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SH, -NH2, -C≡CH, unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy;

[0037] When Z 6 When N, R 3 does not exist; when Z 6 When C, R 3 Selected from -H, -CH3, CHX2, CH2X, -CX3, -(CH2) v OH, -(CH2) v CN, -(CH2) v C≡CH, -OR 16 、-(CH2) v COOH, -(CH2) v NO2, -(CH2) v NR 16 R 17 or-CONR 16 R 17 , R 16 and R 17 Each independently selected from H or C 1-6 Alkyl, X is halogen;

[0038] v = 0, 1, 2, 3, 4;

[0039] Unless otherwise specified, the above-mentioned aryl group contains 6 to 14 carbon atoms; the carbocyclic group contains 3 to 10 carbon atoms and is a non-aromatic structure; the heteroaryl group is a 5-10-membered heteroaryl group; and the heterocyclic group is a 3-10-membered heterocyclic group and is a non-aromatic structure; the heteroaryl group or the heterocyclic group contains one, two or more heteroatoms selected from N, O or S, and the rest are carbon atoms.

[0040] Further, the present invention is as described above 1-6 Alkyl refers to a saturated alkane containing 1, 2, 3, 4, 5 or 6 carbon atoms in the alkyl chain, which can be a straight chain or branched structure, and can be specifically selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight chain or branched pentyl, straight chain or branched hexyl. 1-6 C in alkoxy 1-6 The alkyl moiety has the same definition and selection.

[0041] The aryl group described above in the present invention contains 6 to 14 carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, and is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl.

[0042] As described above, the heteroaryl group of the present invention is a 5- to 10-membered structure, preferably a 5- to 8-membered structure, and more preferably a 5- to 6-membered structure, and is specifically selected from furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, benzofuranyl, benzothiophenyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl or benzophthalazinyl, etc.

[0043] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein A is a 5-6 membered heteroaryl group containing 2-3 heteroatoms selected from N or O; R 1 Independently selected from -F, -Cl or -CH3.

[0044] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein A is selected from pyrazolyl or imidazolyl; Y 1 -CH2-, Y 2 for wherein q is selected from 1 or 2.

[0045] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein A is selected from pyrazolyl or imidazolyl; Y 1 is -(CH2)2-, Y 2 Does not exist.

[0046] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof has a structure represented by formula (II):

[0047]

[0048] in,

[0049] R 18 Independently selected from C 1-6 Alkyl, preferably methyl;

[0050] R 19 The same definition as R in formula (I) 4 ;

[0051] u is 1 or 2;

[0052] The remaining variables are defined the same as in formula (I).

[0053] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof has a structure shown in formula (III):

[0054]

[0055] Among them, R 19 The same definition as R in formula (I) 4 ;

[0056] The remaining variables are defined the same as in formula (I).

[0057] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein when Z 6 When N, R 3 does not exist; when Z 6 When C, R 3 Selected from -H, methyl, ethyl, propyl, isopropyl, -CX3, -(CH2) v OH, -OR 16 、-CH2NR 16 R 17 or-CONR 16 R 17 .

[0058] Further preferably, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein Z 6 C, R 3 For H.

[0059] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein Z 5 For S.

[0060] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from -NR 11 R 12 ;

[0061] R 11 and R 12 Each independently selected from unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy;

[0062] or R 11 and R 12 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S.

[0063] Further, in certain embodiments, the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, wherein R 4 Independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SR 7 、-C(O)R 7 、-C(O)OR 7 、-C(O)NR 7 R 8 、-NR 7 S(O)2R 8 、-NR 7 C(O)R 8 、-NHC(O)NR 7 R 8 , unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy;

[0064] s = 0, 1, 2, 3, 4, 5 or 6;

[0065] R 7 and R 8 Each independently selected from -H, unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy, unsubstituted or s R 10 substituted aryl, unsubstituted or s R 10 substituted heteroaryl, unsubstituted or s R 10 substituted carbocyclic group, unsubstituted or s R10 substituted heterocyclic group;

[0066] or R 7 and R 8 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;

[0067] Each R 9 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SH, -NH2, -C≡CH or C 1-6 Alkoxy;

[0068] Each R 10 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SH, -NH2, -C≡CH, unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy.

[0069] Further, in certain embodiments, in the compound of the present invention as described above or a pharmaceutically acceptable salt thereof, W is -O-.

[0070] The present invention also provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

[0071]

[0072] in,

[0073] X is selected from -(CH2) r -, wherein r is selected from 1, 2, 3, 4 or 5;

[0074] Y does not exist or is wherein q is selected from 1, 2, 3 or 4;

[0075] R 1 Independently selected from -F, -Cl, -Br, -CN, -OR 5 、-NR 5 R 6 、-NO2、-N3、-COOR 5 or-CONR 5 R 6 , R 5 and R 6 Each independently selected from H, C 1-6 alkyl;

[0076] n is 0, 1, 2 or 3;

[0077] A is heteroaryl;

[0078] R 4 Independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, -SR 7 、-(CH2) m C(O)R 7 、-(CH2) m NR 7 R 8 、-(CH2) m S(O)R 7 、-(CH2) m S(O)2R 7 、-(CH2) m OC(O)R 7 、-(CH2) m C(O)OR 7 、-(CH2) m OS(O)2R 7 、-(CH2) m S(O)2OR 7 、-(CH2) m C(O)NR 7 R 8 、-(CH2) m S(O)2NR 7 R 8 、-(CH2) m NR 7 C(O)R 8 、-(CH2) m NR 7 S(O)2R 8 、-(CH2) m NHC(=NH)NR 7 R 8 、-(CH2) m NHC(O)NR 7 R 8 , unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy;

[0079] m = 0, 1, 2, 3, 4;

[0080] s = 0, 1, 2, 3, 4, 5 or 6;

[0081] R 7 and R 8 Each independently selected from -H, -NH2, -OH, unsubstituted or s R9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy, unsubstituted or s R 10 substituted aryl, unsubstituted or s R 10 substituted heteroaryl, unsubstituted or s R 10 substituted carbocyclic group, unsubstituted or s R 10 substituted heterocyclic group;

[0082] or R 7 and R 8 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;

[0083] Each R 9 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH or C 1-6 Alkoxy;

[0084] Each R 10 Each R is independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH, unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 Alkoxy;

[0085] p is 0, 1, 2, 3 or 4;

[0086] W is selected from C, N or O; when W is O, R 3 for not existing;

[0087] R 2 and R 3 are independently selected from -H, -(CH2) w C(O)R 11 、-(CH2) w NR 11 R 12 、-(CH2) w S(O)R 11 、-(CH2) w S(O)2R 11 、-(CH2) w OC(O)R 11 、-(CH2) w C(O)OR 11 、-(CH2) w OS(O)2R11 、-(CH2) w S(O)2OR 11 、-(CH2) w NR 11 C(O)R 12 、-(CH2) w NR 11 S(O)2R 12 、-(CH2) w C(O)NR 11 R 12 、-(CH2) w S(O)2NR 11 R 12 , unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, -(CH2) w R 14 ;

[0088] w = 0, 1, 2, 3, 4;

[0089] t = 0, 1, 2, 3, 4, 5 or 6;

[0090] R 11 and R 12 Each independently selected from -H, -NH2, -OH, unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, unsubstituted or t R 15 substituted aryl, unsubstituted or t R 15 substituted heteroaryl, unsubstituted or t R 15 substituted carbocyclic group, unsubstituted or t R 15 substituted heterocyclic group;

[0091] or R 11 and R 12 The nitrogen atom to which it is attached together forms a 3- to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;

[0092] Each R 13 Each independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH or C 1-6 Alkoxy;

[0093] R 14 Selected from unsubstituted or t R 15substituted aryl, unsubstituted or t R 15 substituted heteroaryl, unsubstituted or t R 15 substituted carbocyclic group, unsubstituted or t R 15 substituted heterocyclic group;

[0094] Each R 15 Each R is independently selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH, unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy;

[0095] Z is selected from O or S;

[0096] Unless otherwise specified, the aryl group described in the above formula (IV) contains 6-14 carbon atoms; the carbocyclic group contains 3-10 carbon atoms and is a non-aromatic structure; the heteroaryl group is a 5-10 membered heteroaryl group; and the heterocyclic group is a 3-10 membered heterocyclic group and is a non-aromatic structure; the heteroaryl group or the heterocyclic group contains one, two or more heteroatoms selected from N, O or S, and the rest are carbon atoms.

[0097] Furthermore, in formula (IV) of the present invention, C 1-6 Alkyl refers to a saturated alkane containing 1, 2, 3, 4, 5 or 6 carbon atoms in the alkyl chain, which may be a straight chain or branched structure, and may be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight chain or branched pentyl, straight chain or branched hexyl. 1-6 C in alkoxy 1-6 The alkyl moiety has the same definition and selection.

[0098] The aryl group in formula (IV) of the present invention contains 6 to 14 carbon atoms, preferably 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms, and is specifically selected from phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl.

[0099] The heteroaryl group in formula (IV) of the present invention is a 5- to 10-membered structure, preferably a 5- to 8-membered structure, and more preferably a 5- to 6-membered structure, and is specifically selected from furan, thiophene, oxazole, thiazole, isoxazole, oxadiazole, thiadiazole, pyrrole, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, phthalazine, quinoline, isoquinoline, pteridine, purine, indole, isoindole, benzofuranyl, benzothiophenyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, benzimidazolyl or benzophthalazinyl, etc.

[0100] Further, in certain embodiments, the compound of formula (IV) of the present invention or a pharmaceutically acceptable salt thereof, wherein A is a 5-6 membered heteroaryl group, the heteroaryl group contains 2-3 heteroatoms, the heteroatoms are selected from N or O; R 1 Independently selected from -F or -Cl.

[0101] Further, in certain embodiments, in the compound of formula (IV) of the present invention or a pharmaceutically acceptable salt thereof, A is selected from pyrazolyl or imidazolyl.

[0102] Further, in certain embodiments, the compound of formula (IV) of the present invention or a pharmaceutically acceptable salt thereof has a structure as shown in formula (V):

[0103]

[0104] in,

[0105] R 1 for -F;

[0106] R 16 Independently selected from C 1-6 Alkyl, preferably methyl;

[0107] u is 1 or 2;

[0108] R 17 Same definition as R 4 ;

[0109] R 1 , R 2 , R 3 , W, Z and n are as shown in the above formula (IV).

[0110] Further, in certain embodiments, the compound of formula (IV) of the present invention or a pharmaceutically acceptable salt thereof has a structure shown in formula (VI):

[0111]

[0112] Among them, R 1 , R 2 , R 3 , W, Z and n are as shown in the above formula (IV), R 17 The definition is as shown in the above formula (V).

[0113] Further, in certain embodiments, in the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, W is selected from N.

[0114] In certain embodiments, in the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, W is selected from O.

[0115] In certain embodiments, the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, wherein W is selected from C.

[0116] Further, in certain embodiments, the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 2 -(CH2) w NR 11 R 12 .

[0117] Preferably, R 2 It is -(CH2)2N(CH3)2.

[0118] Further, in certain embodiments, the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 3 is -H, unsubstituted or t R 13 Substituted C 1-6 Alkyl, R 13 As shown in the above formula (IV).

[0119] Further, in certain embodiments, the compound of formula (IV), formula (V) or formula (VI) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 3 -H or C 1-6 alkyl.

[0120] The compound or its pharmaceutically acceptable salt described in the present invention has the following structure:

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] The invention also provides a pharmaceutical composition.

[0130] The present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.

[0131] Another object of the present invention is to provide the use of the compound or its pharmaceutically acceptable salt or pharmaceutical composition.

[0132] First, the present invention provides the use of the compound or its pharmaceutically acceptable salt or pharmaceutical composition for preparing a drug as an N-myristoyl transferase inhibitor.

[0133] The present invention also provides use of the compound or its pharmaceutically acceptable salt or pharmaceutical composition for preparing a drug for treating or preventing infectious diseases.

[0134] Furthermore, in the above use, the infectious disease includes a protozoan infectious disease or a viral infectious disease.

[0135] Furthermore, in the above use, the protozoan infectious diseases are malaria and leishmaniasis.

[0136] Furthermore, in the above use, the viral infection disease is human rhinovirus infection disease and HIV infection disease.

[0137] In addition, the present invention also provides the use of the compound or its pharmaceutically acceptable salt or pharmaceutical composition for preparing a drug for treating or preventing a hyperproliferative disease.

[0138] Furthermore, in the above use, the hyperproliferative disease is lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer, and colorectal cancer.

[0139] Furthermore, in the above use, the hyperproliferative disease is B-cell lymphoma.

[0140] The present invention provides a method for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0141] Synthesis Scheme 1:

[0142]

[0143] The compound of formula (IV) of the present invention can be obtained by the synthesis method of synthesis scheme 1: compound (a) and compound (b) are heated to react under the catalysis of palladium catalyst to generate compound (c); compound (c) is demethylated under the action of Lewis acid (such as boron tribromide) to obtain compound (d); compound (d) and compound (e) are heated under alkaline conditions to obtain the target product (f). 1 , R 2 , R 3 , R 4, X, A, W, Y, Z, n and p have the meanings as described in formula (IV) of the present invention; LG is a leaving group selected from chlorine, bromine, iodine, methanesulfonyl or p-toluenesulfonyl.

[0144] Synthesis Scheme 2:

[0145]

[0146] The compound of formula (IV) of the present invention can be obtained by the synthesis method of synthesis scheme 2: compound (g) and compound (b) are heated to react under the catalysis of palladium catalyst to generate compound (d); compound (d) and compound (e) are heated under alkaline conditions to obtain the target product (f). 1 , R 2 , R 3 , R 4 , X, A, W, Y, Z, n and p have the meanings as described in formula (IV) of the present invention; LG is a leaving group selected from chlorine, bromine, iodine, methanesulfonyl or p-toluenesulfonyl.

[0147] Synthesis Scheme 3:

[0148]

[0149] The compound of formula (IV) of the present invention can be obtained by the synthesis method of synthesis scheme 3: compound (d) and compound (h) are subjected to Mitsunobu reaction to generate target product (f). 1 , R 2 , R 3 , R 4 , X, A, W, Y, Z, n and p have the meanings as described in formula (IV) of the present invention.

[0150] Synthesis Scheme 4:

[0151]

[0152] The compound of formula (IV) of the present invention can be obtained by the synthesis method of synthesis scheme 4: compound (i) and compound (h) are subjected to Mitsunobu reaction to generate compound (j); compound (j) can be subjected to coupling reaction under the action of palladium catalyst to generate compound (k); compound (k) and compound (b) are reacted under the action of palladium catalyst to generate target product (f). 1 , R 2 , R 3 , R 4 , X, A, W, Y, Z, n and p have the meanings as described in formula (IV) of the present invention.

[0153] The beneficial effects of the present invention are:

[0154] The present invention designs a class of novel structural compounds, which provide a new direction for the development of drugs for anti-protozoan infection or viral infection, especially interference of human rhinovirus, as well as drugs for lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer, and colorectal cancer. In vitro cell antiviral activity studies have shown that these compounds have strong inhibitory effects on both HRV 1B and HRV 14 subtypes of viruses, and also have strong inhibitory effects on a variety of tumor cells. The successful synthesis of the drug compounds disclosed in the present invention expands the drug selection for treating viral infection diseases. In addition, the present invention studies a specific synthesis method, which has a simple process, is easy to operate, and is conducive to large-scale industrial production and application. DETAILED DESCRIPTION

[0155] The following examples are used to further illustrate the present invention, but are not intended to limit the present invention in any form.

[0156] In the embodiments and process routes of the present invention, the letter "A" refers to intermediate A, and the letter "A'" refers to intermediate A', which are not the same concept as A in the compound structures of the claims and the invention content of the present invention.

[0157] Embodiment 1:

[0158]

[0159] Synthesis of intermediate 1a:

[0160] 5-Bromobenzothiophene (1.10 g, 5.16 mmol) was dissolved in 50 mL of dichloromethane, and then 1,1-dichloromethyl ether (0.95 g, 8.33 mmol) and titanium tetrachloride (1.50 g, 7.94 mmol) were added under ice bath, and stirred at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (60 mL) was added to the reaction solution, and dichloromethane was extracted (30 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1-10: 1) to obtain intermediate 1a (0.60 g, yield 48%).

[0161] Synthesis of intermediate 1b:

[0162] The intermediate 1a (0.60 g, 2.47 mmol) was dissolved in 40 mL of dioxane, followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (0.58 g, 3.71 mmol), tetrakistriphenylphosphine palladium (0.20 g, 0.17 mmol) and potassium phosphate trihydrate (0.99 g, 3.71 mmol), and the reaction was stirred at 100°C for 4 hours. TLC monitoring showed that there was no residual raw material. After cooling, water (60 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1-1: 1) to obtain the intermediate 1b (0.30 g, yield 45%).

[0163] Synthesis of intermediate 1c:

[0164] The intermediate 1b (0.30 g, 1.10 mmol) was dissolved in 40 mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (178 mg, 2.20 mmol) and triethylamine (333 mg, 3.30 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (700 mg, 3.30 mmol) was added, stirred at room temperature overnight, and TLC monitoring showed that there was no residual raw material. Water (60 mL) was slowly added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the intermediate 1c (150 mg, yield 45%).

[0165] Synthesis of intermediate A:

[0166] 2-(1,3,5-Trimethyl-1H-pyrazol-4-yl)ethanol (0.77 g, 4.99 mmol) and triethylamine (1.01 g, 9.99 mmol) were added to dichloromethane (20 mL), followed by 4-toluenesulfonyl chloride (1.43 g, 7.49 mmol), and the mixture was reacted at room temperature for 4 hours. TLC monitoring showed that no raw material remained. Water (20 mL) was added to the system, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate A (1.07 g, 73%).

[0167] Synthesis of the final product compound 1:

[0168] Intermediate 1c (150 mg, 0.50 mmol) was dissolved in 30 mL N, N-dimethylformamide, followed by addition of intermediate A (185 mg, 0.60 mmol) and anhydrous potassium carbonate (207 mg, 1.50 mmol), stirred at 50°C for 3 hours, and no raw material remained after TLC monitoring. After cooling, water (40 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain compound 1 (105 mg, yield 48%).

[0169] 1 H NMR (600MHz, CD3OD) δ7.96(s,1H),7.83(d,J=8.4Hz,1H),7.55(s,1H),7.41(d,J=8.4Hz,1H),7.22(s,1H),7.16-7.14( m,2H),3.75(s,2H),3.70(t,J=8.4Hz,2H),3.51(s,3H),2.57(t,J=7.2Hz,2H),2.31(s,6H),1.87(s,3H),1.77(s,3H).

[0170] Embodiment 2:

[0171]

[0172] Synthesis of intermediate 2a:

[0173] The intermediate 1a (0.55 g, 2.27 mmol) was dissolved in 40 mL of dioxane, followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (0.53 g, 3.41 mmol), tetrakistriphenylphosphine palladium (200 mg, 0.17 mmol) and potassium phosphate trihydrate (0.91 g, 3.41 mmol), and the mixture was stirred at 100°C for 2.5 hours. TLC monitoring showed that no raw material remained. After cooling, water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1-1: 1) to obtain the intermediate 2a (250 mg, yield 40%).

[0174] Synthesis of intermediate 2b:

[0175] The intermediate 2a (250 mg, 0.92 mmol) was dissolved in 40 mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (202 mg, 2.50 mmol) and triethylamine (300 mg, 2.97 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (635 mg, 2.97 mmol) was added, stirred at room temperature for overnight, and TLC monitoring showed that there was no residual raw material. Water (60 mL) was slowly added to the reaction solution, and dichloromethane was extracted (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the intermediate 2b (150 mg, yield 54%).

[0176] Synthesis of final product 2:

[0177] Intermediate 2b (150 mg, 0.50 mmol) was dissolved in 30 mL N, N-dimethylformamide, followed by addition of intermediate A (185 mg, 0.60 mmol) and anhydrous potassium carbonate (207 mg, 1.50 mmol), stirred at 50 ° C for 3 hours, and TLC monitoring showed that there was no residual raw material. After cooling, water (40 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain compound 2 (125 mg, yield 57%). MS m / z (ESI): 438.2 [M+1]

[0178] 1 HNMR (600MHz, CD3OD) δ7.88-7.85(m,2H),7.53(s,1H),7.35(d,J=7.8Hz,2H),6.87(d,J=10.8,1H),6.77(t,J=8.4Hz ,1H),4.04(t,J=6.0Hz,2H),3.74(s,2H),3.54(s,3H),2.74(t,J=6.6Hz,2H),2.31(s,6H),1.93(s,3H),1.81(s,3H).

[0179] Embodiment 3:

[0180]

[0181] Synthesis of intermediate 3a:

[0182] The intermediate 1a (0.60 g, 2.47 mmol) was dissolved in 40 mL of dioxane, followed by the addition of 2-hydroxyphenylboronic acid (0.58 g, 3.71 mmol), tetrakistriphenylphosphine palladium (200 mg, 0.17 mmol) and potassium phosphate trihydrate (0.99 g, 3.71 mmol), and the mixture was stirred at 100°C for 2.5 hours. TLC monitoring revealed that no raw material remained. After cooling, water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate =

[0183] 20:1-1:1) to afford intermediate 3a (300 mg, yield 48%).

[0184] Synthesis of intermediate 3b:

[0185] The intermediate 3a (300 mg, 1.18 mmol) was dissolved in 40 mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (191 mg, 2.36 mmol) and triethylamine (357 mg, 3.54 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (706 mg, 3.30 mmol) was added, stirred at room temperature overnight, and TLC monitoring showed that there was no residual raw material. Water (60 mL) was slowly added to the reaction solution, and dichloromethane was extracted (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the intermediate 3b (150 mg, yield 45%).

[0186] Synthesis of the final product compound 3:

[0187] Intermediate 3b (150 mg, 0.59 mmol) was dissolved in 30 mL N,N-dimethylformamide, followed by addition of intermediate A (218 mg, 0.71 mmol) and anhydrous potassium carbonate (244 mg, 1.77 mmol), stirred at 50°C for 3 hours, and no raw material remained after TLC monitoring. After cooling, water (40 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50:1-10:1) to obtain compound 3 (75 mg, yield 34%).

[0188] 1HNMR (600MHz, CDCl3) δ7.96 (m, 2H), 7.90 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.36 (m, 2H), 7.06 (t, J = 7.2Hz, 1H), 6.99 (d, J = 8. 4Hz,1H),4.16(s,2H),3.99(t,J=7.2Hz,2H),3.63(s,3H),2.73(t,J=7.2Hz,2H),2.63(s,6H),2.04(s,3H),1.91(s,3H).

[0189] Embodiment 4:

[0190]

[0191] Synthesis of intermediate 4a:

[0192] The intermediate 1a (320 mg, 1.30 mmol) was dissolved in 7 mL of dioxane, followed by the addition of 3-methyl-2-hydroxyphenylboronic acid (300 mg, 2.00 mmol), tetrakistriphenylphosphine palladium (115 mg, 0.10 mmol) and potassium phosphate trihydrate (692 mg, 2.60 mmol). The system was reacted at 100 ° C for 4 hours under nitrogen protection, and TLC monitoring showed that there was no residual raw material. After cooling, water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 × 3 mL), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain intermediate 4a (311 mg, yield 89%).

[0193] Synthesis of intermediate 4b:

[0194] The intermediate 4a (311 mg, 1.16 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (188 mg, 2.32 mmol) and triethylamine (234 mg, 2.32 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (492 mg, 2.32 mmol) was added, stirred at room temperature for overnight, and TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the intermediate 4b (240 mg, yield 69%).

[0195] Synthesis of the final product compound 4:

[0196] Intermediate 4b (200 mg, 0.67 mmol) was dissolved in 10 mL N,N-dimethylformamide, followed by addition of intermediate A (207 mg, 0.67 mmol) and anhydrous potassium carbonate (180 mg, 1.3 mmol), stirred at 50 ° C for 3 hours, and TLC monitoring showed that there was no residual raw material. After cooling, water (40 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain compound 4 (120 mg, yield 41%). MS m / z (ESI): 434.2 [M+1]

[0197] 1 H NMR(600MHz, CDCl3)δ8.08(s,1H),7.83(d,J=8.4Hz,1H),7.54-7.53(m,1H),7.37(s,1H),7.27-7.24(m,1H),7.18(d,J=6.6Hz,1H),7 .10(t,J=7.2Hz,1H),3.70(s,2H),3.58(s,3H),3.33(t,J=7.2Hz,2H),2.48(t,J=7.2Hz,2H),2.31(s,9H),1.88(s,3H),1.75(s,3H).

[0198] Embodiment 5:

[0199]

[0200] Synthesis of intermediate 5a:

[0201] The intermediate 1a (280 mg, 1.16 mmol) was dissolved in 7 mL of dioxane, followed by the addition of 3-chloro-2-hydroxyphenylboronic acid (300 mg, 1.74 mmol), tetrakistriphenylphosphine palladium (115 mg, 0.10 mmol) and potassium phosphate trihydrate (617 mg, 2.32 mmol). The system was reacted at 100 ° C for 4 hours under nitrogen protection, and TLC monitoring showed that there was no residual raw material. After cooling, water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 × 3 mL), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain intermediate 5a (300 mg, yield 95%).

[0202] Synthesis of intermediate 5b:

[0203] The intermediate 5a (300 mg, 1.00 mmol) was dissolved in 10 mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (162 mg, 2.00 mmol) and triethylamine (202 mg, 2.00 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (424 mg, 2.00 mmol) was added, stirred at room temperature for overnight reaction, and TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the intermediate 5b (240 mg, yield 75%).

[0204] Synthesis of the final product compound 5:

[0205] Intermediate 5b (240 mg, 0.78 mmol) was dissolved in 10 mL N,N-dimethylformamide, followed by addition of intermediate A (280 mg, 0.90 mmol) and anhydrous potassium carbonate (221 mg, 1.60 mmol), and stirred at 50°C for 3 hours. TLC monitoring showed that no raw material remained. After cooling, water (40 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain compound 5 (200 mg, yield 56%). MS m / z (ESI): 454.1 [M+1];

[0206] 1 H NMR (600 MHz, CDCl3) δ 8.07 (s, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.42-7.39 (m, 2H), 7.34-7.32 (m, 1H), 7.14 (t, J = 8.4 Hz, 1H), 3.72 (s, 2H), 3.58 (s, 3H), 3.46 (t, J = 7.8 Hz, 2H), 2.55 (t, J = 7.8 Hz, 2H), 2.33 (s, 6H), 1.86 (s, 3H), 1.78 (s, 3H). Example 6:

[0207]

[0208] Synthesis of intermediate 6a:

[0209] 2-(1,3,5-trimethylpyrazol-4-yl)ethanol (200 mg, 1.30 mmol), 3-bromo-5-fluoropyridin-4-ol (249 mg, 1.30 mmol) and triphenylphosphine (680 mg, 2.59 mmol) were dissolved in 10 mL of tetrahydrofuran, and diethyl azodicarboxylate (452 ​​mg, 2.59 mmol) was added at room temperature, and stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain intermediate 6a (120 mg, yield 28%).

[0210] Synthesis of intermediate B:

[0211] The intermediate 1a (2.66 g, 11.0 mmol) was dissolved in dichloromethane (100 mL), followed by the addition of dimethylamine hydrochloride (1.78 g, 22.0 mmol) and triethylamine (3.33 g, 33.0 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (7.00 g, 33.0 mmol) was added, stirred at room temperature for overnight, and TLC monitoring showed that there was no residual raw material. Water (200 mL) was slowly added to the reaction solution, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride (100 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain intermediate B1 (1.40 g, yield 50%).

[0212] Intermediate B1 (3.00 g, 11.1 mmol) was dissolved in 1,4-dioxane (50 mL), and then diboric acid pinacol ester (4.23 g, 16.6 mmol) was added. The mixture was degassed and purged with nitrogen three times, and then potassium acetate (3.27 g, 33.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (813 mg, 1.10 mmol) were added. Under a nitrogen atmosphere, the mixture was stirred at 100 ° C for 12 hours. TLC monitoring showed that there was no residue of the raw material. The solvent was then removed under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain intermediate B (2.10 g, yield 60%).

[0213] Synthesis of the final product compound 6:

[0214] 6a (120 mg, 0.37 mmol) was dissolved in dioxane (5 mL) and water (1 mL), followed by the addition of intermediate B (139 mg, 0.44 mmol), sodium carbonate (78 mg, 0.73 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (14 mg, 0.018 mmol). The whole system was stirred at 80 ° C for 1 hour. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain compound 6 (19 mg, yield 12%). MS m / z (ESI): 439.1 [M+1]

[0215] 1 H NMR (400MHz, CD3OD) δ8.41(d,J=3.9Hz,1H),8.34(s,1H),7.97(d,J=1.7Hz,1H),7.91(d,J=8.4Hz,1H),7.57(s,1H),7.38(dd,J= 8.4,1.7Hz,1H),4.18(t,J=6.7Hz,2H),3.73(s,2H),3.51(s,3H),2.69(t,J=6.7Hz,2H),2.29(s,6H),1.91(s,3H),1.81(s,3H).

[0216] Embodiment 7:

[0217]

[0218]

[0219] Synthesis of intermediate 7a:

[0220] 5-Bromobenzothiophene (0.60 g, 2.82 mmol) was dissolved in tetrahydrofuran (18 mL). LDA (2 M, 4.2 mL) was slowly added dropwise at -70 °C under nitrogen and stirred at -70 °C for 1 hour. Then iodomethane (800 mg, 5.40 mmol) was added and stirred at -70 °C for 2 hours, then warmed to room temperature and stirred for 13 hours. TLC monitoring showed that there was no residual raw material. 30 mL of water was added to quench the reaction, and dichloromethane was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by thin layer chromatography (ethyl acetate: methanol = 20: 1) to obtain intermediate 7a (0.55 g, yield 86%).

[0221] Synthesis of intermediate 7b:

[0222] The intermediate 7a (0.55 g, 2.38 mmol) was dissolved in dichloromethane (20 mL), and then 1,1-dichloromethyl ether (419 mg, 3.48 mmol) and titanium tetrachloride (690 mg, 3.48 mmol) were added under an ice-water bath, and stirred at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 30: 1-10: 1) to obtain intermediate 7b (0.50 g, yield 82%).

[0223] Synthesis of intermediate 7c:

[0224] The intermediate 7b (0.50 g, 1.96 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of dimethylamine hydrochloride (479 mg, 5.80 mmol) and triethylamine (595 mg, 5.80 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (2.49 g, 11.7 mmol) was added, stirred at room temperature overnight, and TLC monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain intermediate 7c (360 mg, yield 65%).

[0225] Synthesis of intermediate C:

[0226] 2-Bromo-6-fluorophenol (10.0 g, 52.3 mmol), 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (16.2 g, 104.7 mmol) and triphenylphosphine (27.5 g, 104.7 mmol) were dissolved in tetrahydrofuran (70 mL). Under nitrogen protection, diisopropyl azodicarboxylate (21.2 g, 104.7 mmol) was added at 0 ° C. The system was reacted at room temperature for 12 hours. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate C1 (12.0 g, yield 70%).

[0227] The intermediate C1 (2.00 g, 6.1 mmol) and the diboric acid pinacol ester (4.66 g, 18.3 mmol) were dissolved in ethylene glycol dimethyl ether (30 mL), and potassium acetate (1.80 g, 18.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (357.8 mg, 0.49 mmol) were added. The system was placed under nitrogen protection and reacted at 100 ° C for 12 hours. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the system, and dichloromethane was extracted (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate C (2.00 g, yield 61%).

[0228] Synthesis of the final product compound 7:

[0229] Intermediate 7c (316 mg, 0.84 mmol) was dissolved in dioxane (6 mL) and water (1 mL), followed by the addition of intermediate C (200 mg, 0.70 mmol), potassium carbonate (292 mg, 2.10 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (52 mg, 0.07 mmol), the mixture was degassed and purged with nitrogen three times, and then stirred at 100 ° C for 3 hours under a nitrogen atmosphere. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by thin layer chromatography (dichloromethane: methanol = 20: 1) to obtain compound 7 (87 mg, yield 27%). MS m / z (ESI): 452.2 [M+1]

[0230] 1 H NMR (400MHz, CD3OD) δ7.82 (s, 1H) 7.73 (d, J = 8.4Hz, 1H), 7.30 (br d,J=8.0Hz,1H),7.20-7.14(m,1H),7.14-7.08(m,2H),4.55(s,2H),3.81(t,J=6.0Hz,2H),3.71(s,3H),2.87(s,6H),2.69(s,3H),2.64(br t,J=6.0Hz,2H),2.06(s,3H),2.02(s,3H).

[0231] Embodiment 8:

[0232]

[0233] Synthesis of intermediate 8a:

[0234] 5-Bromo-2-fluoroacetophenone (2.00 g, 9.20 mmol) and methyl thioglycolate (1.96 g, 18.4 mmol) were dissolved in 1,4-dioxane (20 mL), and 4-dimethylaminopyridine (5.63 g, 46.0 mmol) was added, and stirred for 20 minutes at room temperature under a nitrogen atmosphere, and then heated to 125 ° C. and stirred for 15 hours. TLC monitoring showed that there was no residual raw material. The residue was poured into water (50 mL) and stirred for 5 minutes, and the mixture was filtered to obtain intermediate 8a (3.10 g, crude product), which was directly used in the next step without purification.

[0235] Synthesis of intermediate 8b:

[0236] Intermediate 8a (3.10 g, crude product) was dissolved in 10 mL of dichloromethane, and N-bromosuccinimide (2.90 g, 16.3 mmol) and benzoyl peroxide (263 mg, 1.00 mmol) were added. Stirring was carried out for 12 hours under nitrogen atmosphere and room temperature. TLC monitoring showed that there was no residue of raw material. The residue was poured into water (30 mL) and stirred for 3 minutes, extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with saturated sodium chloride (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 8b (1.30 g, crude product), which was directly used in the next step without further purification.

[0237] Synthesis of intermediate 8c:

[0238] Intermediate 8b (3.70 g, 10.1 mmol) and dimethylamine hydrochloride (916 mg, 11.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and triethylamine (10 mL) was added. Stir for 12 hours under nitrogen atmosphere and room temperature. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate was added to adjust the pH of the mixture to 9, and the residue was poured into water (60 mL) and stirred for 3 minutes. The mixture was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride aqueous solution (30 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain intermediate 8c (1.14 g, yield 34%).

[0239] Synthesis of intermediate 8d:

[0240] Intermediate 8c (0.10 g, 0.30 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and then intermediate C (228 mg, 0.61 mmol), potassium carbonate (85 mg, 0.61 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (23 mg, 0.03 mmol) were added. Stirring was carried out at 100°C for 3 hours, and no raw material remained after TLC monitoring. Water (10 mL) was added to the reaction solution, and ethyl acetate was extracted (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain intermediate 8d (130 mg, yield 86%).

[0241] Synthesis of the final product compound 8:

[0242] Intermediate 8d (80 mg, 0.16 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (18 mg, 0.48 mmol) was slowly added at 0 ° C. The mixture was stirred at 25 ° C for 2 hours, and the reaction was complete when detected by TLC. Ethyl acetate (2 mL) and sodium sulfate (5.00 g) were added to the mixture and stirred for 5 minutes. Saturated aqueous sodium bicarbonate solution (0.2 mL) was added to the mixture and stirred for 5 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue, which was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain the final product compound 8 (24 mg, yield 32%). MS m / z (ESI): 468.2 [M+1]

[0243] 1 H NMR (400MHz, CD3OD) δ7.88(s,1H),7.80(d,J=8.4Hz,1H),7.38(d,J=8.2Hz,1H),7.23-7.11(m,3H),4.9 1(s,2H),3.75-3.68(m,4H),3.51(s,3H),2.57(t,J=6.8Hz,2H),2.27(s,6H),1.89(s,3H),1.80(s,3H).

[0244] Embodiment 9:

[0245]

[0246] Synthesis of intermediate 9a:

[0247] Intermediate 8c (280 mg, 0.85 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (2 mL), and lithium hydroxide monohydrate (72 mg, 1.70 mmol) was added. The mixture was stirred at 20 ° C for 12 hours, and TLC monitored that there was no residue of raw material. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added with 1M HCl to pH = 7, the mixture was filtered, and the filter cake was concentrated under reduced pressure to obtain intermediate 9a (220 mg, crude product), which was used directly without further purification.

[0248] Synthesis of intermediate 9b:

[0249] Intermediate 9a (210 mg, crude product) was dissolved in N, N-dimethylformamide (6 mL), and HATU (381 mg, 1.0 mmol) and dimethylamine hydrochloride (164 mg, 2.00 mmol), triethylamine (406 mg, 4.00 mmol) were added. The mixture was stirred at 20 ° C for 1 hour, and TLC monitored that there was no residual raw material. Saturated sodium bicarbonate ice water solution (20 mL) was added to quench the reaction, and dichloromethane was extracted (10 mL × 3). The combined organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate 9b (210 mg, crude product) as a yellow solid, which was used directly.

[0250] Synthesis of intermediate 9c:

[0251] Intermediate 9b (200 mg, crude product) was dissolved in THF (3 mL) solution, and diisobutylaluminum hydride (1 M, 1.8 mL) was added. The mixture was stirred at 20 ° C for 2 hours, and TLC monitored that there was no residual raw material. Saturated ammonium chloride in ice water (10 mL) was added to quench the reaction, and ethyl acetate was extracted (10 mL × 3). The combined organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate 9c (182 mg, crude product), which was used directly without further purification.

[0252] Synthesis of the final product compound 9:

[0253] Intermediate 9c (180 mg, crude product), intermediate C (247 mg, 0.66 mmol), potassium carbonate (228 mg, 1.60 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (40 mg, 0.055 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1 mL). The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred under a nitrogen atmosphere at 100 ° C for 3 hours. TLC monitored that there was no residual raw material. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. Compound 9 (44 mg, yield 11%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-15: 1). MS m / z (ESI): 495.2 [M+1]

[0254] 1 H NMR (400MHz, CD3OD) δ8.20(d,J=0.8Hz,1H),8.04(d,J=8.4Hz,1H),7.64(dd,J=8.4,1.4Hz,1H),7.34-7.30(m,1H),7.20- 7.25(m,2H),5.05(s,2H),4.93(s,2H),3.94-3.88(m,5H),3.06(s,6H),3.00(s,6H),2.76(t,J=6.4Hz,2H),2.20(s,6H).

[0255] Embodiment 10:

[0256]

[0257] Synthesis of intermediate 10a:

[0258] Intermediate 8c (250 mg, 0.76 mmol) was dissolved in a methanol solution of dimethylamine (6 mL, 2 M) and stirred at 100°C for 12 hours. TLC monitoring showed that no starting material remained. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain intermediate 10a (235 mg, crude product), which was used directly without further purification.

[0259] Synthesis of the final product compound 10:

[0260] Intermediate 10a (235 mg, crude product), intermediate C (287 mg, 0.77 mmol), potassium carbonate (265 mg, 1.90 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (47 mg, 0.064 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1 mL). The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred for 3 hours under a nitrogen atmosphere at 100 ° C. TLC monitored that there was no residual raw material. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. Column chromatography separation and purification (dichloromethane: methanol = 30: 1-20: 1) gave compound 10 (98 mg, two-step yield 27%). MS m / z (ESI): 509.2 [M+1]

[0261] 1 H NMR(400MHz, CDCl3)8.01(s,1H),7.89(d,J=8.4Hz,1H),7.58-7.53(m,1H),7.18-7.12(m,3H),3.83(s,2H),3 .72(t,J=7.6Hz,2H),3.56(s,3H),3.08(s,6H),2.57(t,J=7.7Hz,2H),2.31(s,6H),1.98(s,3H),1.80(s,3H).

[0262] Embodiment 11:

[0263]

[0264] Synthesis of intermediate 11a:

[0265] (5-Bromo-1-benzothiophene-2-yl)boronic acid (0.70 g, 2.70 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of iodine (622 mg, 2.40 mmol) and potassium fluoride (475 mg, 8.20 mmol). The mixture was stirred at 80 ° C for 4 hours, and TLC monitoring showed that there was no residual raw material. The mixture was poured into a saturated aqueous sodium sulfite solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether) to obtain intermediate 11a (0.60 g, yield 65%).

[0266] Synthesis of intermediate 11b:

[0267] The intermediate 11a (0.30 g, 0.88 mmol) was dissolved in methanol (10 mL), followed by the addition of cuprous iodide (17 mg, 0.088 mmol), potassium carbonate (245 mg, 1.70 mmol) and (1R, 2R)-N, N'-dimethyl 1,2-cyclohexanediamine (32 mg, 0.22 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere, stirred at 60 ° C for 3 hours, and TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether) to obtain the intermediate 11b (150 mg, yield 70%).

[0268] Synthesis of intermediate 11c:

[0269] The intermediate 11b (150 mg, 0.62 mmol) was dissolved in dichloromethane (10 mL), and then 1,1-dichloromethyl ether (142 mg, 1.20 mmol) and titanium tetrachloride (234 mg, 1.20 mmol) were added under ice-water bath, and stirred at room temperature for 2 hours. The reaction was complete after TLC detection. Water (30 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain the intermediate 11c (180 mg, crude product). It was used directly in the next step without purification.

[0270] Synthesis of intermediate 11d

[0271] The intermediate 11c (180 mg, crude product) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of dimethylamine hydrochloride (162 mg, 1.90 mmol) and triethylamine (202 mg, 1.90 mmol). The system was stirred at room temperature for 10 minutes. Acetic acid (80 mg, 1.30 mmol) and sodium triacetoxyborohydride (704 mg, 3.30 mmol) were added to the mixture and stirred at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate: ammonia water = 1: 1: 0.01) to obtain the intermediate 11d (100 mg, two-step yield 50%).

[0272] Synthesis of the final product compound 11

[0273] The intermediate 11d (100 mg, 0.33 mmol) was added to 1,4-dioxane (3 mL) and water (0.3 mL), potassium carbonate (92 mg, 0.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (24 mg, 0.033 mmol) and intermediate C (249 mg, 0.67 mmol). The mixture was degassed and purged with nitrogen three times. The reaction system was reacted at 100 ° C for 3 hours. TLC monitoring showed that there was no residual raw material. After cooling, the solvent was removed under reduced pressure, and the crude product was separated by thin layer chromatography (dichloromethane: ethyl acetate: methanol = 20: 20: 3) to obtain compound 11 (64 mg, yield 38%). MS m / z (ESI): 468.2 [M+1].

[0274] 1 H NMR (400MHz, CD3OD) δ7.82-7.73(m,2H),7.32(d,J=8.0Hz,1H),7.25-7.15(m,3H),4.48(s,2H),4.21(s,3H),3.89(t,J=5.4Hz,2H),3.82(br s,3H),2.92(s,6H),2.73(t,J=5.8Hz,2H),2.14(d,J=11.0Hz,6H).

[0275] Embodiment 12:

[0276]

[0277] Synthesis of intermediate 12a:

[0278] Intermediate 11a (600 mg, 1.70 mmol) and dichloro(methoxy)methane (407 mg, 3.54 mmol) were dissolved in dichloromethane (5 mL), titanium tetrachloride (672 mg, 3.50 mmol) was added, and the mixture was stirred at 25 ° C for 2 hours. TLC monitoring showed that there was no residue of the raw material. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (50 mL). The mixture was stirred for about 30 minutes, extracted with dichloromethane (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride (100 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-0: 1) to obtain intermediate 12a (400 mg, yield 64%).

[0279] Synthesis of intermediate 12b:

[0280] Intermediate 12a (300 mg, 0.82 mmol) and dimethylamine hydrochloride (200 mg, 2.40 mmol) were dissolved in 1,2-dichloromethane (15 mL), and triethylamine (248 mg, 2.40 mmol) was added. The mixture was stirred at 15 ° C for 0.5 hours. Acetic acid (98 mg, 1.63 mmol) and sodium triacetic acid borohydride (693 mg, 3.20 mmol) were added to the mixture. The mixture was stirred at 15 ° C for 2 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0-0: 1) to obtain intermediate 12b (200 mg, yield 62%).

[0281] Synthesis of intermediate 12c:

[0282] The intermediate 12b (60 mg, 0.15 mmol) was dissolved in dimethyl sulfoxide (5 mL), and trifluoromethyltrimethylsilane (65 mg, 0.45 mmol), cuprous iodide (43 mg, 0.23 mmol) and potassium fluoride KF (27 mg, 0.45 mmol) were added under a nitrogen atmosphere. The system was stirred at 100 ° C for 0.5 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain intermediate 12c (120 mg, yield 47%).

[0283] Synthesis of the final product compound 12:

[0284] Intermediate 12c (70 mg, 0.21 mmol) was dissolved in a mixed solution of 1,4-dioxane (6 mL) and water (1 mL), and intermediate C (155 mg, 0.41 mmol), potassium carbonate (89 mg, 0.62 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15 mg, 0.02 mmol) were added. The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. TLC monitoring showed that there was no residue of the raw material. After cooling, the solvent was removed under reduced pressure, and the crude product was separated by thin layer chromatography (dichloromethane: ethyl acetate: methanol = 20:20:3) to obtain compound 12 (80 mg, yield 77%). MS m / z (ESI): 506.2 [M+1].

[0285] 1HNMR (400MHz, CD3OD) δ7.70(d,J=1.0Hz,1H),7.54(d,J=8.4Hz,1H),7.14(dd,J=8.4,1.4Hz,1H),6.88-6.78(m,1H),6.71-6.61(m ,2H),4.33(s,2H),3.37(t,J=6.0Hz,2H),2.75(dt,J=3.2,1.6Hz,3H),2.46(s,6H),2.19(t,J=6.1Hz,2H),1.62(d,J=2.0Hz,6H).

[0286] Embodiment 13:

[0287]

[0288] Synthesis of intermediate 13a:

[0289] 5-Bromo-2-fluoro-3-acetylpyridine (3.00 g, 13.7 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 2-ethyl sulfate (2.92 g, 27.5 mmol), and then under nitrogen atmosphere, 4-dimethylaminopyridine (8.41 g, 68.8 mmol) was added at once. The whole system was stirred at 125 ° C for 12 hours, and TLC monitoring showed that there was no residual raw material. (50 mL of water) was added to the reaction solution and stirred for 5 minutes. Intermediate 13a (2.10 g, yield 53%) was obtained by filtration.

[0290] Synthesis of intermediate 13b:

[0291] The intermediate 13a (2.10 g, 7.30 mmol) was dissolved in a mixed solution of methanol (10 mL), tetrahydrofuran (10 mL) and water (5 mL), followed by the addition of lithium hydroxide monohydrate (616 mg, 14.6 mmol). The whole system was stirred at room temperature for 12 hours, and no raw material remained after TLC monitoring. The solvent was removed by filtration and reduced pressure, and the crude product was poured into water (30 mL), stirred for 5 minutes, and the aqueous phase was extracted with ethyl acetate (20 mL). Hydrochloric acid (1 M) was added to the aqueous phase until pH = 4, the solid was filtered and concentrated in vacuo to obtain the intermediate 13b (2.08 g, crude product).

[0292] Synthesis of intermediate 13c:

[0293] The intermediate 13b (2.08 g, crude product) was dissolved in N-methylpyrrolidone (10 mL), and then cuprous oxide (4.37 g, 30.5 mmol) was added under nitrogen atmosphere. The whole system was stirred at 140°C for 12 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 13c (1.00 g, two-step yield 60%) was obtained.

[0294] Synthesis of intermediate 13d

[0295] The intermediate 13c (0.30 g, 1.30 mmol) was dissolved in carbon tetrachloride (10 mL), followed by the addition of benzoyl peroxide (32 mg, 0.13 mmol) and N-bromosuccinimide (234 mg, 1.30 mmol), and the whole system was stirred for 5 hours at 80 ° C under a nitrogen atmosphere. TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure, water (20 mL) was added, and dichloromethane was extracted (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the intermediate 13d (465 mg, crude product). No purification was required and it was directly used in the next step reaction.

[0296] Synthesis of intermediate 13e

[0297] The intermediate 13d (465 mg, crude product) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of dimethylamine hydrochloride (371 mg, 4.50 mmol) and triethylamine (5 mL), and stirred at room temperature for 12 hours. TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure, water (20 mL) was added, and dichloromethane was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 13e (170 mg, two-step yield 48%) was obtained.

[0298] Synthesis of the final product compound 13:

[0299] Intermediate 13e (0.10 g, 0.37 mmol) was dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL). Intermediate C (276 mg, 0.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27 mg, 0.037 mmol) and potassium carbonate (153 mg, 1.10 mmol) were then added under a nitrogen atmosphere. The mixture was stirred at 100°C for 3 hours. After cooling, the solvent was removed under reduced pressure, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Compound 13 (55 mg, yield 34%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 20:1). MS m / z (ESI): 439.2 [M+1]

[0300] 1 H NMR (400MHz, CD3OD) δ8.76-8.66(m,1H),8.42-8.31(m,1H),7.44-7.38(m,1H),7.21-7.12(m,3H),3.84-3.78(m, 2H),3.64(s,2H),3.61-3.57(m,3H),2.66-2.56(m,2H),2.28-2.25(m,6H),2.01-1.93(m,1H),1.93-1.85(m,1H).

[0301] Embodiment 14:

[0302]

[0303] Synthesis of intermediate 14a:

[0304] 1-(2-bromo-5-fluoropyridin-4-yl)ethanone (1.40 g, 6.40 mmol) was dissolved in 1,4-dioxane (20 mL), followed by the addition of 2-ethyl sulfate (1.36 g, 12.8 mmol), and then 4-dimethylaminopyridine (3.92 g, 32.1 mmol) was added at once under a nitrogen atmosphere. The whole system was stirred at 125°C for 12 hours, and no raw material remained after TLC monitoring. Water (50 mL) was added to the reaction solution, and stirred for 5 minutes, filtered and dried to obtain intermediate 14a (0.68 g, yield 37%).

[0305] Synthesis of intermediate 14b:

[0306] The intermediate 14a (0.68 g, 2.30 mmol) was dissolved in a mixed solution of methanol (10 mL), tetrahydrofuran (10 mL) and water (5 mL), followed by the addition of lithium hydroxide monohydrate (200 mg, 4.70 mmol). The whole system was stirred at room temperature for 12 hours, and no raw material remained after TLC monitoring. The solvent was removed by filtration and reduced pressure, and the crude product was poured into water (30 mL), stirred for 5 minutes, extracted with ethyl acetate (20 mL), and hydrochloric acid (1 M) was added to the aqueous phase until pH = 4, the solid was filtered and concentrated in vacuo to obtain the intermediate 14b (0.32 g, crude product).

[0307] Synthesis of intermediate 14c:

[0308] Intermediate 14b (0.27 g, 0.99 mmol) was dissolved in N-methylpyrrolidone (10 mL), and then cuprous oxide (568 mg, 3.90 mmol) was added under nitrogen atmosphere. The whole system was stirred at 140°C for 12 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 14c (0.10 g, yield 44%) was obtained.

[0309] Synthesis of intermediate 14d:

[0310] The intermediate 14c (0.10 g, 0.44 mmol) was dissolved in carbon tetrachloride (5 mL), followed by the addition of benzoyl peroxide (11 mg, 0.044 mmol) and N-bromosuccinimide (78 mg, 0.44 mol). The whole system was stirred at 80 ° C for 5 hours under nitrogen atmosphere. TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure, water (20 mL) was added, and dichloromethane was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the intermediate 14d (0.18 g, crude product). It was used directly in the next step without purification.

[0311] Synthesis of intermediate 14e

[0312] Intermediate 14d (0.18 g, crude product) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of dimethylamine hydrochloride (144 mg, 1.70 mmol) and triethylamine (356 mg, 3.50 mmol), and stirred at room temperature for 12 hours. TLC monitoring showed that no raw material remained. The solvent was removed under reduced pressure, water (20 mL) was added, and dichloromethane was extracted (10 mL×3). The organic phases were combined, washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (ethyl acetate: methanol: ammonia water = 10:1:0.05) to obtain intermediate 14e (40 mg, two-step yield 32%).

[0313] Synthesis of the final product compound 14:

[0314] Intermediate 14e (40 mg, 0.15 mmol) was dissolved in a mixed solution of 1,4-dioxane (5 mL) and water (0.5 mL), and then intermediate C (110 mg, 0.30 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (11 mg, 0.015 mmol) and potassium carbonate (61 mg, 0.44 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 100°C for 3 hours. After cooling, the solvent was removed under reduced pressure, water (20 mL) was added, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (0.04% hydrochloric acid)-acetonitrile]; B%: 15%-33%, 10 min) to obtain compound 14 (17 mg, yield 26%). MS m / z (ESI): 439.2 [M+1]

[0315] 1 H NMR(400MHz,DMSO-d6)δ11.12(br s,1H),9.61-9.49(m,1H),8.93-8.72(m,1H),8.61-8.45(m,1H),7.55-7.38(m,2H),7.33-7.23(m,1H),4.72-4.60(m,2H),3.99(br t,J=6.8Hz,2H),3.56(br s,3H),2.79-2.71(m,6H),2.61-2.57(m,2H),2.00-1.94(m,3H),1.93-1.86(m,3H).

[0316] Embodiment 15:

[0317]

[0318] Synthesis of intermediate 15a:

[0319] 5-bromosalicylaldehyde (1.50 g, 7.50 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of tetrafluoroboric acid-ether adduct (0.12 g, 0.70 mmol) and then dropwise addition of ethyl diazoacetate (1.40 g, 12.0 mmol) at a temperature below 38 °C. The whole system was stirred at room temperature for 10 minutes, and TLC monitoring showed that there was no residue of the raw material. Concentration under reduced pressure gave a yellow oil. Concentrated sulfuric acid (2.5 mL) was slowly added to the oil, and then reacted at room temperature for 10 minutes, and the color turned brown. The mixture was diluted with dichloromethane (30 mL), and sodium bicarbonate (15.00 g) was added in batches. The whole system was stirred at room temperature for 20 hours, filtered and concentrated to give a yellow oil intermediate 15a (1.90 g, yield 97%).

[0320] Synthesis of intermediate 15b

[0321] The intermediate 15a (0.80 g, 3.10 mmol) was dissolved in dioxane (30 mL), and then 3-fluoro-2-hydroxyphenylboronic acid (0.70 g, 3.72 mmol), tetrakistriphenylphosphine palladium (285 mg, 0.22 mmol), and potassium phosphate trihydrate (1.40 g, 4.70 mmol) were added. The system was heated to 100°C under nitrogen protection and reacted for 4 hours. TLC monitoring showed that there was no residual raw material. The system was cooled to room temperature and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1-1:1) to obtain the intermediate 15b (600 mg, yield 67%).

[0322] Synthesis of intermediate 15c

[0323] The intermediate 15b (600 mg, 2.10 mmol) was dissolved in (25 mL) tetrahydrofuran (25 mL), and then lithium aluminum hydride (80 mg, 2.10 mmol) was added and stirred at room temperature. TLC monitoring showed that there was no residual raw material. A small amount of water was added to the reaction solution, and then silica gel was added to stir the sample. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-10: 1) to obtain the intermediate 15c (250 mg, yield 46%).

[0324] Synthesis of intermediate 15d

[0325] The intermediate 15c (250 mg, 1.00 mmol) was dissolved in dichloromethane (20 mL), and then phosphorus tribromide (0.15 mL, 1.00 mmol) was added under ice bath, and the system was reacted at room temperature for 3 hours. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, the pH value was adjusted to alkaline, and dichloromethane was extracted (10 mL×2), the organic phases were combined, washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the intermediate 15d (250 mg, yield 80%).

[0326] Synthesis of intermediate 15e

[0327] Intermediate 15d (250 mg, 0.78 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of N,N-diisopropylethylamine (0.2 g, 1.5 mmol) and dimethylamine (42 mg, 0.94 mmol), and the whole system was stirred at room temperature for reaction, and TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure to obtain intermediate 15e (150 mg, yield 68%).

[0328] Synthesis of the final product compound 15

[0329] Intermediate 15e (150 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by addition of intermediate A (0.20 g, 0.63 mmol) and potassium carbonate (146 mg, 1.10 mmol), and the whole system was stirred at 50 ° C for reaction, and TLC monitoring showed that there was no residual raw material. 50 mL of water was added to the reaction solution, extracted with ethyl acetate (25 mL × 3), the organic phases were combined, washed with saturated sodium chloride (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain compound 15 (100 mg, yield 45%). MS m / z (ESI): 422.1 [M+1]

[0330] 1 H NMR (600MHz, CDCl3) δ7.78(s,1H), δ7.67(s,1H), δ7.47(d,J=8.4Hz, 1H), δ7.42(d,J=8.4Hz, 1H), δ7.15(t,J=4.8Hz, 1H), δ7.08(d,J=6.6Hz, 1H) ,δ7.07(d,J=6.0Hz,1H),δ3.69(t,J=7.8Hz,2H),δ3.67(s,2H),δ3.58(s ,3H), δ2.57(t,J=7.8Hz,2H), δ2.35(s,6H), δ1.94(s,3H), δ1.85(s,3H).

[0331] Embodiment 16:

[0332]

[0333] Synthesis of intermediate 16a:

[0334] Intermediate 1b (300 mg, 1.10 mmol) was dissolved in dichloromethane (20 mL), and then methylamine hydrochloride (222 mg, 2.75 mmol) and triethylamine (333 mg, 3.30 mmol) were added, and the mixture was stirred at room temperature for 5 hours, and then sodium acetate borohydride (706 mg, 3.30 mmol) was added, and the mixture was stirred at room temperature overnight. TLC monitoring showed that there was no residual raw material. Water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain intermediate 16a (180 mg, yield 57%).

[0335] Synthesis of the final product compound 16:

[0336] Intermediate 16a (180 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide (10 mL), and then intermediate A (213 mg, 0.69 mmol) and anhydrous potassium carbonate (214 mg, 1.55 mmol) were added, and stirred at 50°C for 3 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 16 (120 mg, yield 45%) was obtained. MS m / z (ESI): 424.2 [M+1]

[0337] 1 HNMR (600MHz, CDCl3) δ7.84(d,J=7.8Hz,2H),7.69(s,1H),7.40(d,J=6.6Hz,1H),7.11-7.00(m,3H),4.05 (s,2H),3.72(t,J=7.2Hz,2H),3.34(s,3H),2.68(s,3H),2.56(t,J=7.2Hz,2H),2.00(s,3H),1.70(s,3H).

[0338] Embodiment 17:

[0339]

[0340] Synthesis of intermediate 17a:

[0341] Intermediate 1b (600 mg, 2.10 mmol) was dissolved in N,N-dimethylformamide (30 mL), and then intermediate A (358 mg, 1.16 mmol) and anhydrous potassium carbonate (314 mg, 2.27 mmol) were added. The mixture was stirred at 50°C for 3 hours. After the reaction, water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (30 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 50:1-15:1) to obtain intermediate 17a (205 mg, yield 46%).

[0342] Synthesis of the final product compound 17:

[0343] The intermediate 17a (205 mg, 0.50 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of dimethylamine hydrochloride, dimethyl-D6-amine hydrochloride (91 mg, 1.10 mmol) and triethylamine (167 mg, 1.65 mmol), stirred at room temperature for 5 hours, and then sodium acetate borohydride (350 mg, 1.65 mmol) was added, stirred at room temperature overnight, and TLC monitoring showed that there was no residual raw material. Water (30 mL) was slowly added to the reaction solution, extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with saturated sodium chloride (25 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 50: 1-15: 1) to obtain compound 17 (150 mg, yield 68%). MS m / z (ESI): 444.2 [M+1]

[0344] 1 H NMR (600MHz, CD3OD) δ7.96(s,1H),7.83(d,J=8.4Hz,1H),7.55(s,1H),7.41(d,J=8.4Hz,1H),7.22(s,1H),7.16 -7.14(m,2H),3.75(s,2H),3.70(t,J=8.4Hz,2H),3.51(s,3H),2.57(t,J=7.2Hz,2H),1.87(s,3H),1.77(s,3H).

[0345] Embodiment 18:

[0346]

[0347] Synthesis of compound 18:

[0348] Compound 16 (100 mg, 0.23 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of bromoacetonitrile (33 mg, 0.28 mmol) and N,N-diisopropylethylamine (61 mg, 0.47 mmol), and the system was stirred at room temperature for 3 hours. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL × 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography separation and purification (dichloromethane: methanol = 30: 1) gave compound 18 (60 mg, yield 56%). MS m / z (ESI): 449.1 [M+1]

[0349] 1 H NMR (600MHz, CDCl3) δ8.00 (s, 1H), δ7.85 (d, J=8.4Hz, 1H), δ7.47 (d, J=

[0350] 8.4Hz, 1H), δ7.44 (s, 1H), δ7.16 (d, J = 1.8Hz, 1H), δ7.11-7.10 (m, 2H), δ3.86 (s, 2H), δ

[0351] 3.72(t,J=7.2Hz,2H), δ3.61(s,3H), δ3.46(s,2H), δ2.59(t,J=7.2Hz,2H), δ2.47(s,3H), δ1.96(s,3H), δ1.85(s,3H).

[0352] Embodiment 19:

[0353]

[0354] Synthesis of compound 19:

[0355] Compound 16 (100 mg, 0.23 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of cyanogen bromide (30 mg, 0.28 mmol) and N,N-diisopropylethylamine (61 mg, 0.47 mmol), and the system was stirred at room temperature for 3 hours. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution, and dichloromethane was extracted (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was separated and purified by column chromatography (dichloromethane: methanol = 30: 1) to obtain compound 19 (60 mg, yield 57%). MS m / z (ESI): 463.1 [M+1]

[0356] 1H NMR (600MHz, CDCl3) δ7.89 (d, J = 7.8Hz, 1H), δ7.85 (d, J = 8.4Hz, 1H), δ7.53 (d, J = 8.4Hz, 1H), δ7.49 (s, 1H), δ7.18 (s, 1H), δ7.13-7. 10(m,2H), δ4.41(s,2H), δ3.75(t,J=7.2Hz,2H), δ3.57(s,3H), δ2.85(s,3H), δ2.59(t,J=7.2Hz,2H), δ1.96(s,3H), δ1.85(s,3H).

[0357] Embodiment 20:

[0358]

[0359] Synthesis of intermediate 20a:

[0360] 5-Bromo-3-(chloromethyl)benzothiophene (0.50 g, 1.91 mmol) was dissolved in dimethyl sulfoxide (8 mL), and potassium cyanide (249 mg, 3.80 mmol) was slowly added. The reaction was stirred at 25 ° C for 3 hours, and TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction system, and ethyl acetate was extracted (20 mL × 3). The combined organic phase was washed with saturated sodium chloride aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. It was separated and purified by column chromatography (petroleum ether: ethyl acetate = 100: 1-10: 1) to obtain intermediate 20a (0.29 g, yield 60%).

[0361] Synthesis of intermediate 20b:

[0362] Intermediate 20a (200 mg, 0.79 mmol) was dissolved in tetrahydrofuran (6 mL) solution, and nickel (23 mg, 0.40 mmol) was added under nitrogen atmosphere. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred at 30 ° C for 10 hours under hydrogen atmosphere, and TLC monitored the raw material without residue. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 20b (200 mg, crude product). The crude product does not need to be further purified.

[0363] Synthesis of the final product compound 20:

[0364] Intermediate 20b (150 mg, crude product) was dissolved in 1,4-dioxane (6 mL) and water (1 mL), and intermediate C (395 mg, 1.00 mmol), potassium carbonate (219 mg, 1.58 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39 mg, 0.053 mmol) were added. The mixture was degassed and purged with nitrogen three times, and then the mixture was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. TLC monitored that there was no residual raw material. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20: 1-15: 1) to obtain compound 20 (34 mg, two-step yield 12%). MS m / z (ESI): 452.2 [M+1]

[0365] 1 H NMR (400 MHz, CDCl3) δ 7.78-7.92 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 7.16 -7.21 (m, 1H), 7.09-7.15 (m, 2H), 3.71 (t, J = 7.6 Hz, 2H), 3.56 (s, 3H), 3.04-3.14 (m, 2H), 2.76-2.84 (m, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.44 (s, 6H), 1.94 (s, 3H), 1.81 (s, 3H). Example 21:

[0366]

[0367] Synthesis of intermediate 21a:

[0368] 5-Bromobenzothiophene-3-carboxylic acid (400 mg, 1.56 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by the addition of dimethylamine hydrochloride (151 mg, 1.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (357 mg, 1.87 mmol), 1-hydroxybenzotriazole (252 mg, 1.87 mmol) and triethylamine (787 mg, 7.80 mmol). The system was stirred at room temperature for 3 hours, and TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 21a (300 mg, yield 68%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 30: 1-20: 1).

[0369] Synthesis of intermediate 21b:

[0370] The intermediate 21a (300 mg, 1.06 mmol) was dissolved in dioxane (30 mL), followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (200 mg, 1.27 mmol), tetrakistriphenylphosphine palladium (61 mg, 0.05 mmol) and potassium phosphate (420 mg, 1.58 mmol), and the atmosphere was replaced with nitrogen three times to place the entire system under a nitrogen atmosphere. The system was refluxed and stirred at 100 ° C for 4 hours, and no raw material remained after TLC monitoring. The reaction solution was concentrated under reduced pressure and directly separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain the intermediate 21b (250 mg, yield 75%).

[0371] Synthesis of intermediate 21c:

[0372] Intermediate 21b (250 mg, 0.79 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by addition of intermediate A (292 mg, 0.95 mmol) and potassium carbonate (218 mg, 1.58 mmol), and the whole system was stirred at 50°C for reaction, and TLC monitoring showed that no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and separated and purified by column chromatography (dichloromethane: methanol = 15:1) to obtain intermediate 21c (214 mg, yield 60%).

[0373] Synthesis of the final product compound 21:

[0374] The intermediate 21c (214 mg, 0.47 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (60 mg, 1.41 mmol) was slowly added at -20 ° C. The whole system was heated to 0 ° C and stirred overnight. TLC monitoring showed that there was no residual raw material. Ice water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 21 (89 mg, yield 43%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 20: 1). MS m / z (ESI): 440.2 [M+1]

[0375] 1H NMR (600MHz, CD3OD) δ7.96(s,1H),7.83(d,J=8.4Hz,1H),7.55(s,1H),7.41(d,J=8.4Hz,1H),7.22(s,1H),7.16 -7.14(m,2H),3.70(t,J=8.4Hz,2H),3.51(s,3H),2.57(t,J=7.2Hz,2H),2.31(s,6H),1.87(s,3H),1.77(s,3H).

[0376] Embodiment 22:

[0377]

[0378] Synthesis of intermediate 22a:

[0379] The intermediate 1b (0.30 g, 1.10 mmol) was dissolved in dichloromethane (50 mL), and then two drops of concentrated hydrochloric acid were added. After 30 minutes, tetrahydropyrrole (0.157 g, 2.20 mmol) was added. The whole system was stirred at room temperature for 5 hours, and then sodium acetate borohydride (0.71 g, 3.3 mmol) was added. The reaction was allowed to proceed overnight at room temperature. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 22a (0.30 g, yield 86%) was obtained.

[0380] Synthesis of final product 22:

[0381] Intermediate 22a (0.30 g, 0.90 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by addition of intermediate A (0.30 g, 1.00 mmol) and potassium carbonate (0.20 g, 1.40 mmol), and the whole system was stirred at 50 ° C for reaction, and TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 22 (400 mg, yield 92%) was obtained. MS m / z (ESI): 464.2 [M+1]

[0382] 1H NMR (600MHz, CDCl3) δ7.89 (d, J=7.8Hz, 1H), δ7.85 (s, 1H), δ7.59 (d, J=7.8Hz, 1H), δ7.24-7.19 (m, 4H), δ3.81 (t, J=7. 2Hz, 2H), 3.61 (s, 3H), δ3.57 (s, 2H), δ2.65 (t, J = 7.2Hz, 2H), δ2.36 (m, 4H), δ2.12 (m, 4H), δ1.99 (s, 3H), δ1.94 (s, 3H).

[0383] Embodiment 23:

[0384]

[0385] Synthesis of intermediate 23a:

[0386] The intermediate 1b (0.30 g, 1.10 mmol) was dissolved in dichloromethane (50 mL), and azetidine hydrochloride (206 mg, 2.20 mmol) and triethylamine (0.33 g, 3.30 mmol) were added. The whole system was stirred at room temperature for 5 hours, and then sodium acetate borohydride (0.71 g, 3.30 mmol) was added. The reaction was allowed to proceed overnight at room temperature. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and dichloromethane was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 23a (327 mg, yield 95%) was obtained.

[0387] Synthesis of the final product compound 23:

[0388] Intermediate 23a (327 mg, 1.05 mmol) was dissolved in N, N-dimethylformamide (60 mL), followed by addition of intermediate A (0.40 g, 1.30 mmol) and potassium carbonate (0.46 g, 3.30 mmol), and the whole system was stirred at 50 ° C for reaction, and TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and dichloromethane was extracted (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 23 (400 mg, yield 82%) was obtained. MS m / z (ESI): 450.2 [M+1].

[0389] 1H NMR (600MHz, CD3Cl) δ7.90 (s, 1H), δ7.82 (d, J = 8.4Hz, 1H), δ7.50 (s, 1H), δ7.41 (d, J = 8.4Hz 1H), δ7.22 (t, J = 4.8Hz, 1H), δ7.15 (t, J = 5.4Hz, 2H), δ3.89 (s, 2H), 3.70 (t, J = 7.2Hz, 2H), δ3.5 1 (s, 3H), δ3.43-3.38 (m, 4H), δ2.57 (t, J = 7.2Hz, 2H), δ2.14 (m, 2H) δ1.88 (s, 3H), δ1.79 (s, 3H).

[0390] Embodiment 24:

[0391]

[0392] Synthesis of intermediate 24a:

[0393] 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (1.00 g, 6.40 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (3.03 g, 7.10 mmol) was added at 0 ° C. The mixture was stirred at 15 ° C for 2 hours, and TLC monitored that there was no residual raw material. Saturated aqueous sodium bicarbonate solution (30 mL) was added to quench the reaction and stirred for 0.5 hours. Dichloromethane extraction (30 mL × 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 50: 1-3: 1) to obtain intermediate 24a (0.53 g, yield 55%).

[0394] Synthesis of intermediate 24b:

[0395] Intermediate 24a (0.30 g, 2.00 mmol) and 2-bromo-6-fluoro-aniline (449 mg, 2.40 mmol) were dissolved in methanol (10 mL), and sodium cyanoborohydride (372 mg, 5.90 mmol) and acetic acid (118 mg, 2.00 mmol) were added. The mixture was stirred at 15 ° C for 10 hours, and TLC monitored that there was no residue left. Water (5 mL) was added to the system to quench, and the solvent was removed under reduced pressure to obtain a residue. The residue was diluted with dichloromethane (20 mL) and washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and purified by column chromatography (ethyl acetate) to obtain intermediate 24b (80 mg, yield 12%).

[0396] Synthesis of the final product compound 24:

[0397] Compound 24b (80 mg, 0.25 mmol) was dissolved in dioxane (3 mL) and water (0.3 mL), and intermediate B (117 mg, 0.37 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (18 mg, 0.025 mmol) and potassium carbonate (68 mg, 0.49 mmol) were added, and the mixture was degassed and purged with nitrogen three times. The mixture was stirred at 100 ° C for 10 hours, and TLC monitored that there was no residual raw material. The mixture was filtered and the filtrate was concentrated in vacuo to obtain a residue. Column chromatography separation and purification (dichloromethane-dichloromethane: methanol = 20: 1) gave compound 24 (22 mg, yield 20%). MS m / z (ESI): 437.2 [M+1]

[0398] 1 H NMR (600MHz, CDCl3) δ7.94-7.81(m,2H),7.37(br s,1H),7.29(br s,1H),7.03(dd,J=12.0,8.4Hz,1H),6.97(br d,J=7.2Hz,1H),6.86-6.79(m,1H),3.66(br s,2H),3.54(s,3H),3.15(br s, 2H), 2.45 (t, J = 7.2Hz, 2H), 2.29 (s, 6H), 2.03 (s, 3H), 1.85 (s, 3H). Embodiment 25:

[0399]

[0400] Synthesis of intermediate 25a:

[0401] Ethyl 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)acetate (3.00 g, 15.3 mmol) was dissolved in toluene (100 mL), followed by the addition of tetrabutylammonium iodide (2.82 g, 7.64 mmol), potassium carbonate (7.61 g, 55.0 mmol) and paraformaldehyde (4.59 g, 152.8 mmol). The mixture was stirred at 80 ° C for 24 hours, and no raw material remained after TLC monitoring. The mixture was filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 20:1-ethyl acetate: methanol = 30:1) to obtain intermediate 25a (0.50 g, yield 16%).

[0402] Synthesis of intermediate 25b:

[0403] Trimethylsulfoxide iodide (740 mg, 3.40 mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium hydride (125 mg, 3.10 mmol, 60% content) was added at 0°C under nitrogen. The mixture was stirred at 20°C for 1 hour. The mixture was added dropwise to a mixture of intermediate 25a (0.5 g, 2.4 mmol) in dimethyl sulfoxide (5 mL) at 0°C under nitrogen. The mixture was stirred at 20°C for 10 hours, and no raw material remained after TLC monitoring. Water (30 mL) was added to the reaction solution, and extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 25b (0.30 g, yield 56%) was obtained.

[0404] Synthesis of intermediate 25c:

[0405] Intermediate 25b (0.25 g, 1.2 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (85.37 mg, 2.3 mmol) was added at 0 ° C under a nitrogen atmosphere. The mixture was stirred at 20 ° C for 3 hours, and TLC monitored that there was no residue of the raw material. Ethyl acetate (10 mL) was added to the mixture, and sodium sulfate (10 g), water (0.1 mL) and saturated sodium bicarbonate (0.1 mL) were added and stirred for 10 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 25c (0.40 g, crude product). It was used directly in the next step without purification.

[0406] Synthesis of intermediate 25d:

[0407] Intermediate 25c (0.25 g, 1.40 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (421 mg, 4.20 mmol), and at 0 ° C, methylsulfonyl chloride (318 mg, 2.80 mmol) was added dropwise to the mixture. The mixture was stirred at 25 ° C for 2 hours, and TLC monitored that there was no residue of the raw material. The mixture was poured into water (30 mL) and dichloromethane (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 25d (0.40 g, crude product). It was used directly in the next step without purification.

[0408] Synthesis of intermediate 25e:

[0409] Intermediate 25d (0.40 g, 1.60 mmol) and 2-bromo-6-fluoro-phenol (444 mg, 2.30 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by the addition of potassium carbonate (428 mg, 3.10 mmol). The mixture was stirred at 80°C for 3 hours, and no raw material remained after TLC monitoring. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 25e (250 mg, yield 44%) was obtained.

[0410] Synthesis of the final product compound 25:

[0411] Intermediate 25e (100 mg, 0.28 mmol) and intermediate B (180 mg, 0.57 mmol) were dissolved in dioxane (5 mL) and water (0.5 mL). Potassium carbonate (79 mg, 0.57 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 0.028 mmol) were added under a nitrogen atmosphere. The mixture was stirred at 100 ° C for 3 hours, and TLC monitoring showed that there was no residual raw material. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The preparation was separated by column chromatography (dichloromethane-dichloromethane: methanol = 20: 1) to obtain compound 25 (35 mg, yield 24%). MS m / z (ESI): 464.2 [M+1]

[0412] 1 H NMR (400MHz, CD3OD) δ8.13(s,1H),8.02(s,1H),7.92(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,1H),7.25-7.14(m,3H),4. 68(s,2H),3.80(s,3H),3.65(s,2H),2.93(s,6H),2.25(s,3H),2.21(s,3H),0.88-0.83(m,2H),0.73-0.69(m,2H).

[0413] Embodiment 26:

[0414]

[0415] Synthesis of intermediate 26a:

[0416] 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2.00 g, 14.2 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by the addition of N-bromosuccinamide (2.79 g, 15.7 mmol). The mixture was stirred at room temperature for 2 hours, and the desired mass was detected by LCMS. The mixture was concentrated in vacuo. The crude product intermediate 26a (3.10 g, crude) was obtained as a brown oil.

[0417] Synthesis of intermediate 26b:

[0418] Intermediate 26a (3.10 g, 14.1 mmol) was dissolved in N, N-dimethylformamide (30 mL), followed by the addition of ammonium chloride (2.27 g, 42.4 mmol), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (8.07 g, 21.2 mmol) and triethylamine (7.16 g, 70.7 mmol). The mixture was stirred at room temperature for 1 hour, and TLC monitored that the raw material was not left. The mixture was poured into water (90 mL) and stirred for 5 minutes. The reaction mixture was distributed between ethyl acetate (50 mL) and saturated sodium chloride aqueous solution (50 mL). The organic phase was separated, washed with saturated ammonium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain intermediate 26b (6.50 g, crude product). The residue was used directly without further purification.

[0419] Synthesis of intermediate 26c:

[0420] Intermediate 26b (6.50 g, 29.8 mmol) was dissolved in dichloromethane (150 mL), and N,N-diisopropylethylamine (23.12 g, 178.8 mmol) and phosphorus oxychloride (13.71 g, 89.4 mmol) were added. The mixture was stirred at 15 °C for 3 hours, and no raw material remained after TLC monitoring. The reaction mixture was concentrated under reduced pressure, water (50 mL) was added, and ethyl acetate was extracted (50 mL × 3). The combined organic phase was washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-0: 1) to obtain intermediate 26c (1.10 g, yield 19%).

[0421] Synthesis of intermediate 26d:

[0422] Intermediate 26c (1.10 g, 5.50 mmol) was dissolved in dioxane (10 mL) and water (1 mL), followed by the addition of potassium vinyl trifluoroborate (1.10 g, 8.20 mmol), cesium carbonate (3.58 g, 11.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (403 mg, 0.55 mmol), degassed and purged with nitrogen three times, and then the mixture was stirred at 110 °C for 12 hours under a nitrogen atmosphere, and LCMS showed that the desired mass was detected. Concentrated under reduced pressure, water (30 mL) was added to the mixture, extracted with ethyl acetate (30 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 26d (0.70 g, yield 86%).

[0423] Synthesis of intermediate 26e:

[0424] Intermediate 26d (0.70 g, 4.70 mmol) was dissolved in dioxane (20 mL), and 9-boranebicyclo[3.3.1]nonane (0.5 M tetrahydrofuran solution, 19.0 mL) was added under nitrogen atmosphere. The mixture was heated to 100 ° C and stirred for 10 hours. The mixture was cooled to 20 ° C, and ethanol (2.19 g, 47.5 mmol) and sodium hydroxide (6 M, 1.3 mL) were added to the mixture. The mixture was stirred for 30 minutes, and then hydrogen peroxide (944 mg, 8.30 mmol, 30% purity) was added dropwise. The mixture was stirred at 80 ° C for 2 hours, and LCMS showed that the reaction was complete. Saturated sodium sulfite aqueous solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1-0:1) to obtain intermediate 26e (0.75 g, yield 96%).

[0425] Synthesis of intermediate 26f:

[0426] The intermediate 26e (150 mg, 0.91 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of triphenylphosphine (715 mg, 2.70 mmol) and 2-bromo-6-fluorophenol (347 mg, 1.80 mmol), and at 0°C, diisopropyl azodicarboxylate (551 mg, 2.70 mmol) was added. The mixture was heated to 40°C and stirred for 10 hours. TLC monitoring showed that no raw material remained. The mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the intermediate 26f (180 mg, yield 59%).

[0427] Synthesis of the final product compound 26:

[0428] Intermediate 26f (180 mg, 0.53 mmol) was dissolved in dioxane (8 mL) and water (1 mL), followed by the addition of intermediate B (186 mg, 0.59 mmol), potassium carbonate (221 mg, 1.60 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39 mg, 0.053 mmol). The mixture was degassed and purged with nitrogen three times, and then stirred at 100 ° C for 10 hours under a nitrogen atmosphere. TLC monitored that there was no residual raw material. The reaction solution was filtered and concentrated under reduced pressure, and purified by column chromatography (dichloromethane-dichloromethane: methanol = 20: 1) to obtain compound 26 (20 mg, yield 17%). MS m / z (ESI): 449.2 [M+1]

[0429] 1 H NMR (400MHz, CD3OD) δ7.88(s,1H),7.80(br d,J=8.4Hz,1H),7.54(s,1H),7.35(br d,J=9.2Hz,1H),7.23-7.12(m,3H),3.92(br t,J=6.0Hz,2H),3.74(s,2H),3.59(s,3H),2.74(br t,J=5.6Hz,2H),2.30(s,6H),1.85(s,3H).

[0430] Embodiment 27:

[0431]

[0432] Synthesis of intermediate 27a:

[0433] Intermediate 26 (100 mg, 0.22 mmol) was dissolved in tetrahydrofuran (5 mL) solution, and lithium aluminum hydride (17 mg, 0.45 mmol) was added at 0 ° C. The mixture was stirred at 75 ° C for 3 hours, and TLC monitored that there was no residue of raw material. The reaction was quenched with water (5 mL), and the reaction mixture was concentrated under reduced pressure to remove the solvent to obtain intermediate 27a (80 mg, crude product), which was used in the next step without further purification.

[0434] Synthesis of the final product compound 27:

[0435] The intermediate 27a (80 mg, crude product) was dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (90 mg, 0.88 mmol), and acetyl chloride (28 mg, 0.35 mmol) was added dropwise at 0°C. The mixture was stirred at 20°C for 2 hours. TLC monitoring revealed that no raw material remained. The solvent was removed by concentration under reduced pressure, and the mixture was separated and purified by column chromatography (dichloromethane-dichloromethane: methanol = 20:1) to obtain compound 27 (29 mg, 2-step yield 27%). MS m / z (ESI): 495.2 [M+1]

[0436] 1 H NMR (400MHz, CD3OD) δ7.94 (s, 1H), 7.82 (d, J = 8.4Hz, 1H), 7.75-7.60 (m, 1H), 7.54 (s, 1H), 7.39 (br d,J=8.4Hz,1H),7.26-7.20(m,1H),7.19-7.13(m,2H),4.13(s,2H),3.78-3.71(m ,4H),3.55(s,3H),2.65(t,J=6.6Hz,2H),2.30(s,6H),1.86(s,3H),1.75(s,3H).

[0437] Embodiment 28:

[0438]

[0439] Synthesis of compound 28:

[0440] Intermediate 27a (100 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of triethylamine (0.3 mL), and at 0°C, methylsulfonyl chloride (51 mg, 0.04 mmol) was added dropwise, and the mixture was stirred at 20°C for 2 hours. TLC showed that the starting material was completely consumed. The solvent was removed by concentration under reduced pressure, and the product was separated and purified by column chromatography (dichloromethane-dichloromethane: methanol = 20:1) to obtain compound 28 (31 mg, yield 26%). MS m / z (ESI): 531.2 [M+1]

[0441] 1H NMR (400MHz, CD3OD) δ7.92(d,J=1.2Hz,1H),7.82(d,J=8.3Hz,1H),7.55(s,1H),7.38(dd,J=8.3,1.2Hz,1H),7.24-7.14( m,3H),4.02(s,2H),3.82(t,J=6.4Hz,2H),3.75(s,2H),3.58(s,3H),2.80(s,3H),2.71(s,2H),2.31(s,6H),1.81(s,3H).

[0442] Embodiment 29:

[0443]

[0444] Synthesis of intermediate 29a:

[0445] Ethyl 1,5-dimethylpyrazole-3-carboxylate (10.00 g, 58.27 mmol) was dissolved in 1,2-dichloroethane (100 mL), followed by the addition of N-bromosuccinamide (20.74 g, 116.5 mmol), and stirred at 80 ° C under nitrogen for 16 hours. The mixture was cooled to 25 ° C. Water (200 mL) was added to the system, extracted with dichloromethane (200 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain intermediate 29a (11.0 g, yield 75%).

[0446] Synthesis of intermediate 29b:

[0447] Intermediate 29a (10.00 g, 39.66 mmol) was dissolved in a solution of ethylene glycol dimethyl ether (400 mL) and water (40 mL), followed by (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (9.43 g, 47.6 mmol), cesium carbonate (38.77 g, 119.0 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.45 g, 1.98 mmol) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled to 25° C. Water (500 mL) was added to the reaction system, extracted with ethyl acetate (500 mL×3), washed with saturated sodium chloride (300 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain intermediate 29b (5.00 g, yield 52%).

[0448] Synthesis of intermediate 29c:

[0449] Intermediate 29b (4.50 g, 18.51 mmol) was dissolved in tetrahydrofuran (45 mL) solution, and hydrochloric acid (6 M, 30 mL) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 3 hours, and TLC monitoring showed that no raw material remained. Water (150 mL) was added to the reaction system, extracted with ethyl acetate (150 mL×3), washed with saturated sodium chloride (100 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 29c (4.00 g, yield 92%).

[0450] Synthesis of intermediate 29d:

[0451] Intermediate 29c (4.00 g, 17.12 mmol) was dissolved in ethanol (40 mL) solution, and sodium borohydride (1.62 g, 42.82 mmol) was added in batches at 0°C. The resulting mixture was stirred at 25°C for 1 hour, and no raw material remained after TLC monitoring. Water (150 mL) was added to the reaction system, extracted with ethyl acetate (150 mL×3), washed with saturated sodium chloride (100 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate 29d (2.50 g, yield 67%).

[0452] Synthesis of intermediate 29e:

[0453] Intermediate 29d (1.00 g, 4.62 mmol) was dissolved in dichloromethane (10 mL), and methylsulfonyl chloride (793 mg, 6.93 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 25°C for 2 hours, and no raw material remained after TLC monitoring. Water (50 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (50 mL×3), washed with saturated sodium chloride (40 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 29e (1.20 g, yield 81%).

[0454] Synthesis of the final product compound 29:

[0455] Intermediate 29e (0.12 g, 0.37 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by addition of intermediate 1c (112 mg, 0.37 mmol) and cesium carbonate (364 mg, 1.12 mmol), stirred at 100 ° C under nitrogen atmosphere for 16 hours, and TLC monitoring showed that no raw material remained. The mixture was cooled to 25 ° C. Water (30 mL) was added to the reaction system, extracted with ethyl acetate (30 mL × 3), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound 29 (100 mg, yield 53%). MS: (m / z, ESI): 496.2 [M+1]

[0456] 1 H NMR (600MHz, DMSO-d6) δ8.02 (s, 1H), 7.96 (d, J = 8.4Hz, 1H), 7.60 (s, 1H), 7.42-7.40 (m, 1H), 7.27-7.24 (m, 1H), 7.20-7.16 (m, 1H) ),4.09-4.08(m,2H),3.80-3.79(m,2H),3.63-3.62(m,5H),2.83-2.82(m,2H),2.15(s,6H),1.81(s,3H),1.31(t,J=7.2Hz,3H).

[0457] Embodiment 30:

[0458]

[0459] Synthesis of compound 30:

[0460] Compound 29 (1.00 g, 1.98 mmol) was dissolved in tetrahydrofuran (20 mL) solution, and lithium aluminum hydride (0.79 mL, 1.98 mmol, 2.5 M THF solution) was added dropwise at 0°C. Stir at 0°C for 1 hour. The reaction was quenched with sodium sulfate decahydrate (2.87 g) at 0°C. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (20 mL×3), the filtrate was concentrated under reduced pressure, and the filtrate was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the final product 30 (94 mg, yield 10%). MS m / z (ESI): 454.2 [M+1]

[0461] 1H NMR (400MHz, CDCl3) δ7.92(d,J=1.6Hz,1H),7.81(d,J=8.3Hz,1H),7.45(dd,J=8.4,1.7Hz,1H),7.33(s,1H),7.17-7.0 5(m,3H),4.18(s,2H),3.75(t,J=7.3Hz,2H),3.63(d,J=27.3Hz,5H),2.60(t,J=7.3Hz,2H),2.31(s,6H),1.87(s,3H).

[0462] Embodiment 31:

[0463]

[0464] Synthesis of intermediate 31a:

[0465] Compound 30 (550 mg, 1.09 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of triethylamine (331 mg, 3.27 mmol), and at 0°C, methylsulfonyl chloride (188 mg, 1.64 mmol) was added dropwise. The resulting mixture was stirred at 25°C for 30 minutes. Water (50 mL) was added to the reaction system, extracted with dichloromethane (50 mL×3), washed with saturated sodium chloride (40 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 31a (300 mg, yield 52%).

[0466] Synthesis of the final product compound 31:

[0467] Intermediate 31a (300 mg, 0.57 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of sodium methanolsulfinate (117 mg, 1.14 mmol), and the solution was stirred at 25°C for 24 hours. Water (30 mL) was added to the reaction system, extracted with ethyl acetate (30 mL×3), washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 31 (72 mg, yield 24%). MS m / z (ESI): 516.2 [M+1]

[0468] 1H NMR(400MHz, CDCl3)δ:7.97(d,J=1.6Hz,1H),7.78(d,J=8.4Hz,1H),7.39(dd,J=8.4,1.7Hz,1H),7.32(s,1H),7.18-7.10(m,1H),7.13 -7.03(m,2H),4.08(s,2H),3.82(t,J=6.7Hz,2H),3.64(d,J=8.3Hz,5H),2.83(s,3H),2.74(t,J=6.7Hz,2H),2.28(s,6H),1.84(s,3H).

[0469] Embodiment 32:

[0470]

[0471] Compound 26 (100 mg, 0.22 mmol) was dissolved in water (0.2 mL) and ethanol (2 mL), followed by the addition of acetaldehyde oxime (1 mL), triphenylphosphine (12 mg, 0.045 mmol) and palladium acetate (5 mg, 0.022 mmol). The resulting mixture was stirred at 80 ° C for 5 hours, and TLC monitored that there was no residue of the raw material. The reaction mixture was concentrated under reduced pressure to remove the solvent. Column chromatography separation and purification (dichloromethane-dichloromethane: methanol = 20: 1) gave compound 32 (42 mg, yield 39%). MS m / z (ESI): 467.2 [M+1]

[0472] 1 H NMR(400MHz,CD3OD)δ7.89(s,1H),7.82-7.80(m,1H),7.52(s,1H),7.36-7.34(m,1H),7.19-7.11(m,3 H),3.96(t,J=6.4Hz,2H),3.73(s,2H),3.61(s,3H),2.92(t,J=6.4Hz,2H),2.29(s,6H),1.84(s,3H).

[0473] Embodiment 33:

[0474]

[0475] Compound 29 (140 mg, 0.28 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (4 mL), and lithium hydroxide (120 mg, 2.80 mmol) and water (1 mL) were added. The system was left to react overnight at room temperature, and TLC monitoring revealed that no raw material remained. The system was concentrated, and the crude product was separated and purified by thin-plate chromatography (dichloromethane: methanol = 10: 1) to obtain intermediate 33a (100 mg, yield 76%).

[0476] The intermediate 33a (50 mg, 0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N, N, N', N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and dimethylamine hydrochloride (10 mg, 0.12 mmol) was added. The reaction system was reacted at room temperature for two hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 33 (32 mg, yield 65%). MS: (m / z, ESI): 495.2 [M+1]

[0477] 1 H NMR (400MHz, DMSO-d6) δ8.02(s,1H),7.97(d,J=8.0Hz,1H),7.60(s,1H),7.43(d,J=8.0Hz,1H),7.14-7.31(m,3H),3.81(t,J=6.4Hz,2H),3.62(br s,2H),3.60(s,3H),2.91(br s,3H),2.84(br s,3H),2.66(br s,2H),2.17(s,6H),1.82(s,3H).

[0478] Embodiment 34:

[0479]

[0480] Intermediate 33a (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (27 mg, 0.12 mmol) was added. The reaction system was reacted at room temperature for two hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 34 (40 mg, yield 62%). MS:(m / z,ESI):642.2[M+1]

[0481] 1 H NMR(600MHz,DMSO-d6)δ7.98(s,1H),7.93(br,1H),7.57(s,1H),7.38-7.37(m,1H),7.23-7.17(m,3H),5.27(s,1H),4.91( s,1H),413-4.11(m,3H),4.03(s,1H),3.85-3.81(m,2H),3.63-3.60(m,5H),2.73(s,2H),2.14(s,6H),1.83-1.78(m,3H).

[0482] Embodiment 35:

[0483]

[0484] Compound 29 (100 mg, 0.20 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), and hydroxylamine aqueous solution (50%, 133 mg, 2.00 mmol) and sodium hydroxide (16 mg, 0.40 mmol) were added, and the system was reacted at room temperature for 8 hours. TLC monitoring showed that there was no residue of the raw material. The reaction system was concentrated, and the crude product was separated and purified by thin plate chromatography (dichloromethane: methanol = 10: 1) to obtain compound 35 (40 mg, yield 41%). MS: (m / z, ESI): 483.2 [M+1]

[0485] 1 H NMR (600MHz, DMSO-d6) δ10.61(s,1H),8.73(s,1H),8.03(s,1H),7.99(d,J=8.4Hz,1H),7.60(s,1H),7.45-7.43(m,1H),7.27-7. 25(m,1H),7.19-7.16(m,2H),3.88(t,J=7.2Hz,2H),3.63(s,2H),3.60(s,3H),2.82(t,J=7.2Hz,2H),2.16(s,6H),1.82(s,3H).

[0486] Embodiment 36:

[0487]

[0488] Intermediate 33a (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and morpholine (26 mg, 0.30 mmol) was added. The reaction system was reacted at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain compound 36 (30 mg, yield 53%). MS: (m / z, ESI): 537.2 [M+1]

[0489] 1 H NMR(600MHz, DMSO-d6)δ7.99(s,1H),7.94(d,J=8.4Hz,1H),7.60(s,1H),7.41-7.39(m,1H),7.28-7.24(m,1H),7.21-7.17( m,2H),3.81(t,J=7.2Hz,2H),3.61(s,2H),3.58(s,3H),3.49-3.48(m,6H),2.67(t,J=7.2Hz,2H),2.16(s,6H),1.82(s,3H).

[0490] Embodiment 37:

[0491]

[0492] The intermediate 33a (50 mg, 0.10 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N, N, N', N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and aniline (28 mg, 0.30 mmol) was added. The reaction system was reacted at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL × 3), washed with saturated sodium chloride (10 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The compound 37 (30 mg, yield 56%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 10: 1). MS: (m / z, ESI): 543.2 [M+1]

[0493] 1H NMR(600MHz, DMSO-d6)δ9.72(s,1H),8.02(s,1H),7.96(d,J=7.8Hz,1H),7.73-7.72(m,1H),7.57(s,1H),7.43-7.42(m,1H),7.27-7.24(m,3 H),7.19-7.16(m,2H),7.03-7.00(m,1H),4.01(t,J=7.2Hz,2H),3.68(s,3H),3.59(s,2H),2.91(t,J=7.2Hz,2H),2.12(s,6H),1.83(s,3H).

[0494] Embodiment 38:

[0495]

[0496] Intermediate 33a (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and 2-aminopyridine (28 mg, 0.30 mmol) was added. The reaction system was reacted at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 38 (20 mg, yield 37%). MS: (m / z, ESI): 543.2 [M+1]

[0497] 1 H NMR (600MHz, DMSO-d6) δ9.19 (s, 1H), 8.30-8.29 (m, 1H), 8.06 (d, J = 8.4Hz, 1H), 7. 97(s,1H),7.93(d,J=8.4Hz,1H),7.80-7.79(m,1H),7.55(s,1H),7.39(d,J=1.2H z,1H),7.27-7.24(m,1H),7.17-7.16(m,2H),7.12-7.10(m,1H),3.92(t,J=7.2Hz ,2H),3.69(s,3H),3.55(s,2H),2.92(t,J=7.2Hz,2H),2.10(s,6H),1.87(s,3H).

[0498] Embodiment 39:

[0499]

[0500] Intermediate 33a (50 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and 3-aminopyrazole (25 mg, 0.30 mmol) was added. The reaction system was reacted at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 39 (25 mg, yield 47%). MS: (m / z, ESI): 533.2 [M+1]

[0501] 1 H NMR (600MHz, CD3OD) δ7.86 (s, 1H), 7.79 (d, J = 8.4Hz, 1H), 7.58-7.53 (m, 2H), 7.33 (d, J = 7.8Hz, 1H), 7.17-7. 13(m,4H),4.01(t,J=6.0Hz,2H),3.74(s,2H),3.68(s,3H),2.97(t,J=6.0Hz,2H),2.31(s,6H),1.95(s,3H).

[0502] Embodiment 40:

[0503]

[0504] Intermediate 33a (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and methylamine hydrochloride (9 mg, 0.12 mmol) was added. The reaction system was reacted at room temperature for two hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 40 (30 mg, yield 65%). MS: (m / z, ESI): 481.2 [M+1]

[0505] 1 H NMR (600MHz, CDCl3) δ7.92 (s, 1H), δ7.75 (d, J = 8.4Hz, 1H), δ7.36 (d, J = 7.2Hz, 1H), δ7.10 (d, J = 6.0Hz, 1H), δ7.07-7.04 (m, 2H), δ6.71 (d, J = 4 .2Hz,1H), δ4.09(t,J=6.6Hz,2H), δ3.75(s,2H), δ3.60(s,3H), δ3.00(t,J=6.6Hz,2H), δ2.86(d,J=5.4Hz,3H), δ2.35(s,6H), δ1.85(s,3H).

[0506] Embodiment 41:

[0507]

[0508] Intermediate 33a (50 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 mL), triethylamine (20 mg, 0.2 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50 mg, 0.13 mmol) were added, the system was reacted at room temperature for 10 minutes, and aminoacetonitrile (7 mg, 0.12 mmol) was added. The reaction system was reacted at room temperature for two hours. TLC monitoring showed that there was no residual raw material. Water (10 mL) was added to the reaction system, extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride (10 mL×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain compound 41 (32 mg, yield 63%). MS: (m / z, ESI): 506.2 [M+1]

[0509] 1 H NMR (600MHz, CDCl3) δ7.91 (s, 1H), δ7.79 (d, J = 7.8Hz, 1H), δ7.37 (d, J = 7.8Hz, 1H), δ7.13-7.07 (m, 4H), δ4.22 (d, J = 6 .0Hz,2H), δ4.03(t,J=6.0Hz,2H), δ3.64(s,3H), δ2.96(t,J=6.0Hz,2H), δ2.46(s,6H), δ1.92(s,3H), δ1.63(s,2H).

[0510] Embodiment 42:

[0511]

[0512] Synthesis of intermediate 42a:

[0513] 33a (200 mg, 0.43 mmol) was dissolved in N,N-dimethylformamide (5 mL), triethylamine (87 mg, 0.86 mmol) and 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (212 mg, 0.56 mmol) were added, the system was reacted at room temperature for 10 minutes, and Boc-glycine (67 mg, 0.51 mmol) was added. The reaction system was reacted at room temperature for 2 hours. TLC monitoring showed that there was no residual raw material. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain 42a (160 mg, yield 64%).

[0514] Synthesis of final product 42:

[0515] 42a (160 mg, 0.27 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added. The system was left to react overnight at room temperature. TLC monitoring showed that no raw material remained. The solvent was removed under reduced pressure and purified by column chromatography (dichloromethane: methanol = 10:1) to obtain the final product 42 (70 mg, yield 50%). MS: (m / z, ESI): 525.2 [M+1]

[0516] 1 H NMR(600MHz,DMSO-d6)δ8.11(s,1H),8.02-8.01(m,1H),7.93(br,1H),7.87(s,1H),7.49-7.47(m,1H),7.29-7.25(m,1H),7.22-7.19(m,1H), 7.18-7.16(m,1H),4.17(br,2H),3.87(t,J=7.2Hz,2H),3.78(d,J=6.0Hz,2H),3.62(s,3H),2.82(t,J=7.2Hz,2H),2.51(s,6H),1.82(s,3H).

[0517] Embodiment 43:

[0518]

[0519] Synthesis of intermediate 43a

[0520] 3-Fluoro-2-hydroxyphenylboronic acid (300 mg, 1.92 mmol) was dissolved in dioxane (30 mL), followed by the addition of 7b (400 mg, 1.57 mmol), tetrakistriphenylphosphine palladium (127 mg, 0.10 mmol) and potassium phosphate (837 mg, 3.14 mmol), and the atmosphere was replaced with nitrogen three times to place the entire system under a nitrogen atmosphere. The system was refluxed and stirred at 100 ° C for 4 h, and no raw material remained after TLC monitoring. The reaction solution was directly separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 43a (380 mg, yield 84%). MS m / z (ESI): 286.9 [M+1]

[0521] Synthesis of intermediate 43b

[0522] 43a (380 mg, 1.33 mmol) was dissolved in methanol (30 mL), followed by the addition of methylamine hydrochloride (178 mg, 2.66 mmol) and triethylamine (335 mg, 3.32 mmol). The whole system was reacted at room temperature for 2 h, and NaBH4 (101 mg, 2.66 mmol) was added to the above reaction solution, and stirring was continued for 1 h. TLC detected that no raw material remained. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 2) to obtain 43b (200 mg, yield 50%). MS m / z (ESI): 301.9 [M+1]

[0523] Synthesis of intermediate 43c

[0524] 43b (200 mg, 0.66 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by the addition of intermediate A (290 mg, 0.80 mmol) and potassium carbonate (182 mg, 1.32 mmol), and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was followed until no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 43c (150 mg, yield 46%). MS m / z (ESI): 496.2 [M+1]

[0525] Synthesis of final product 43

[0526] 43c (150 mg, 0.30 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and then LiAlH4 (23 mg, 0.60 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was followed until no raw material remained. Water (5 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the final product 43 (100 mg, yield 74%). MS m / z (ESI): 454.1 [M+1]

[0527] 1 H NMR (600 MHz, DMSO-d6) δ 7.93 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.41 (dd, J = 1.8 Hz, J = 1.8 Hz, 1H), 7.30-7.26 (m, 2H), 7.21-7.18 (m, 1H), 4.86 (s, 1H), 4.18 (s, 2H), 3.96 (s, 2H), 3.79 (t, J = 7.8 Hz, 2H), 3.52 (s, 3H), 2.62-2.59 (m, 5H), 2.37 (s, 3H), 1.79 (s, 3H). Example 44:

[0528]

[0529] Synthesis of intermediate 44a

[0530] 43a (380 mg, 1.33 mmol) was dissolved in methanol (30 mL), followed by the addition of dimethylamine hydrochloride (215 mg, 2.66 mmol) and triethylamine (335 mg, 3.32 mmol). The whole system was reacted at room temperature for 2 h, and NaBH4 (101 mg, 2.66 mmol) was added to the above reaction solution, and stirring was continued for 1 h. TLC detected that no raw material remained. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-1: 2) to obtain 44a (250 mg, yield 60%). MS m / z (ESI): 315.9 [M+1]

[0531] Synthesis of intermediate 44b

[0532] 44a (250 mg, 0.79 mmol) was dissolved in N,N-dimethylformamide (25 mL), followed by addition of 29e (276 mg, 0.95 mmol) and potassium carbonate (218 mg, 1.58 mmol), and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was performed until no raw material remained. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL × 2). The organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 44b (200 mg, yield 50%). MS m / z (ESI): 510.2 [M+1]

[0533] Synthesis of final product 44

[0534] 44b (200 mg, 0.39 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and then LiAlH4 (30 mg, 0.78 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was followed until no raw material remained. Water (5 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the final product 44 (100 mg, yield 55%). MS m / z (ESI): 454.1 [M+1]

[0535] 1 H NMR(600MHz, DMSO-d6)δ7.92(s,1H),7.87(d,J=8.4Hz,1H),7.38(d,J=8.4Hz,1H),7.29-7.25(m,1H),7.22-7.1(m,2H),4.67(s,1H), 4.19(d,J=3.6Hz,2H),3.77(t,J=7.8Hz,2H),3.55(s,2H),3.52(s,3H),2.62(t,J=7.8Hz,2H),2.50(s,3H),2.15(s,6H),1.75(s,3H).

[0536] Embodiment 45:

[0537]

[0538] Synthesis of intermediate 45a:

[0539] 21b (250 mg, 0.79 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and LiAlD4 (30 mg, 1.58 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was performed until no raw material remained. Water (5 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 45a (150 mg, yield 63%). MS m / z (ESI): 304.1 [M+1]

[0540] Synthesis of intermediate 45b:

[0541] 45a (150 mg, 0.50 mmol) was dissolved in N, N-dimethylformamide (25 mL), 29e (174 mg, 0.60 mmol) and potassium carbonate (138 mg, 1.00 mmol) were added, and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was followed until no raw material remained. Water (50 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL × 2). The organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 45b (100 mg, yield 40%). MS m / z (ESI): 498.1 [M+1]

[0542] Synthesis of final product 45:

[0543] 45b (100 mg, 0.20 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and then LiAlH4 (15 mg, 0.40 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was performed until no raw material remained. Water (5 mL) was added to the reaction solution, and it was extracted with ethyl acetate (25 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15:1) to obtain the final product 45 (50 mg, yield 55%). MS m / z (ESI): 456.1 [M+1]

[0544] 1H NMR(600MHz,DMSO-d6)δ8.05(s,1H),8.00(d,J=8.4Hz,1H),7.61(s,1H),7.47-7.45(m,1H),7.30-7.26(m,1H),7.24-7.1 8(m,2H),4.67(s,1H),4.19(s,2H),3.77(t,J=7.8Hz,2H),3.51(s,3H),2.62(t,J=7.8Hz,2H),2.18(s,6H),1.74(s,3H).

[0545] Embodiment 46:

[0546]

[0547] Synthesis of intermediate 46a:

[0548] 4-Bromothiophenol (8.00 g, 42.8 mmol) was dissolved in dichloromethane (100 mL), ethyl 4-chloroacetoacetate (7.00 g, 42.8 mmol) and triethylamine (6.50 g, 63.5 mmol) were added, and the whole system was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 50:1-30:1) to obtain 46a. (12.00 g, yield 89%). MS m / z (ESI): 317.2 [M+1]

[0549] Synthesis of intermediate 216b:

[0550] Polyphosphoric acid (40.00 g) was added to toluene (100 mL), followed by 46a (12.00 g, 38.0 mmol), and the whole system was stirred at 100°C for 10 h. The supernatant of the reaction solution was purified by column chromatography (petroleum ether: ethyl acetate = 40:1-20:1) to obtain 46b (6.80 g, yield 60%). MS m / z (ESI): 299.2 [M+1]

[0551] Synthesis of intermediate 46c:

[0552] 46b (6.80 g, 22.7 mmol) was dissolved in carbon tetrachloride (100 mL), followed by the addition of NBS (4.90 g, 27.3 mmol) and benzoyl peroxide (8.0 mg, 0.03 mmol), and the whole system was refluxed and stirred for 8 h. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 60:1-30:1) to obtain 46c (6.00 g, yield 70%). MS m / z (ESI): 377.2 [M+1]

[0553] Synthesis of intermediate 46d:

[0554] 46c (500 mg, 1.33 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of dimethylamine hydrochloride (129 mg, 1.59 mmol) and triethylamine (269 mg, 2.66 mmol). The whole system was stirred at room temperature for 2 h. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 46d (350 mg, yield 77%). MS m / z (ESI): 342.1 [M+1]

[0555] Synthesis of intermediate 46e:

[0556] 46d (350 mg, 1.03 mmol) was dissolved in dioxane (40 mL), followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (192 mg, 1.23 mmol), tetrakistriphenylphosphine palladium (83 mg, 0.07 mmol) and potassium phosphate (548 mg, 2.06 mmol), and the atmosphere was replaced with nitrogen three times to place the entire system under a nitrogen atmosphere. The system was refluxed and stirred at 100 ° C for 4 h, and no raw material remained after TLC monitoring. The reaction solution was directly separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 2) to obtain 46e (250 mg, yield 65%). MS m / z (ESI): 374.1 [M+1]

[0557] Synthesis of intermediate 46f:

[0558] 46e (250 mg, 0.67 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by the addition of A (220 mg, 0.67 mmol) and potassium carbonate (185 mg, 1.34 mmol), and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was performed until no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, the organic phases were backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 46f (250 mg, yield 66%). MS m / z (ESI): 568.1 [M+1]

[0559] Synthesis of final product 46:

[0560] 46f (250 mg, 0.44 mmol) was also added to anhydrous tetrahydrofuran (25 mL), and then LiAlH4 (33 mg, 0.88 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was followed until no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the final product 46 (100 mg, yield 47%). MS m / z (ESI): 484.1 [M+1]

[0561] 1 H NMR(600MHz,DMSO-d6)δ8.11(d,J=1.2Hz,1H),8.00(d,J=8.4Hz,1H),7.61(s,1H ),7.46(dd,J=1.8Hz,J=1.2Hz,1H),7.30-7.28(m,1H),7.27-7.20(m,2H),4.74( t,J=5.4Hz,1H),4.67(t,J=5.4Hz,1H),4.18(d,J=4.8Hz,2H),3.92(d,J=4.8Hz, 2H),3.75(s,3H),3.74(s,3H),2.61(t,J=7.2Hz,2H),2.21(s,6H),1.75(s,3H).

[0562] Embodiment 47:

[0563]

[0564] Synthesis of intermediate 47a:

[0565] 46c (500 mg, 1.33 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by the addition of methylamine hydrochloride (107 mg, 1.60 mmol) and triethylamine (269 mg, 2.66 mmol). The whole system was stirred at room temperature for 2 h. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-2: 1) to obtain 47a (350 mg, yield 81%). MS m / z (ESI): 328.1 [M+1]

[0566] Synthesis of intermediate 47b:

[0567] 47a (350 mg, 1.07 mmol) was dissolved in dioxane (40 mL), followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (200 mg, 1.27 mmol), tetrakistriphenylphosphine palladium (61 mg, 0.05 mmol) and potassium phosphate (420 mg, 1.58 mmol), and the atmosphere was replaced with nitrogen three times to place the entire system under a nitrogen atmosphere. The system was refluxed and stirred at 100 ° C for 4 h, and no raw material remained after TLC monitoring. The reaction solution was directly separated and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 2) to obtain 47b (255 mg, yield 66%). MS m / z (ESI): 360.1 [M+1]

[0568] Synthesis of intermediate 47c:

[0569] 47b (255 mg, 0.71 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by the addition of intermediate A (312 mg, 0.85 mmol) and potassium carbonate (196 mg, 1.42 mmol), and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was performed until no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (dichloromethane: methanol = 30: 1-15: 1) to obtain 47c (250 mg, yield 64%). MS m / z (ESI): 554.1 [M+1]

[0570] Synthesis of final product 47:

[0571] 47c (250 mg, 0.45 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and then LiAlH4 (34 mg, 0.90 mmol) was added. The whole system was stirred at room temperature for reaction, and TLC monitoring was followed until no raw material remained. Water (5 mL) was added to the reaction solution, and ethyl acetate was extracted (25 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain 47 (115 mg, yield 55%). MS m / z (ESI): 470.1 [M+1]

[0572] 1H NMR (600MHz, DMSO-d6) δ8.12(d,J=1.2Hz,1H),8.00(d,J=8.4Hz,1H),7.61( s,1H),7.46(dd,J=1.8Hz,J=1.2Hz,1H),7.30-7.28(m,1H),7.27-7.20(m,2H ),4.98(s,1H),4.69(s,1H),4.18(s,2H),4.12(s,1H),3.79-3.75(m,2H),3 .67(s,1H),3.57-3.52(m,4H),2.61-2.59(m,2H),2.27(s,3H),1.76(s,3H).

[0573] Embodiment 48:

[0574]

[0575] Synthesis of final product 48:

[0576] 43b (200 mg, 0.66 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by the addition of intermediate D (290 mg, 0.80 mmol) and potassium carbonate (182 mg, 1.32 mmol), and the whole system was stirred at 60 ° C for reaction, and TLC monitoring was performed until no raw material remained. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (25 mL × 2), the organic phases were combined, the organic phases were backwashed with water (25 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the final product 48 (150 mg, yield 46%). MS m / z (ESI): 496.2 [M+1]

[0577] 1 H NMR (600MHz, DMSO-d6) δ7.93 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.30-7.25 (m, 2H), 7.21 (dd, J = 6.0Hz, J = 4.8Hz,1H),3.97(s,2H),3.87(t,J=6.6Hz,2H),3.67(s,3H),2.71(t,J=6.6Hz,2H),2.60(s,1H),2.51(s,3H),2.38(s,3H).

[0578] Embodiment 49:

[0579]

[0580] Synthesis of intermediate 49a:

[0581] 48 (500 mg, 1.11 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of di-tert-butyl dicarbonate (292 mg, 1.34 mmol) and triethylamine (224 mg, 2.22 mmol), and the whole system was stirred at room temperature for 1.5 h. TLC monitoring showed that there was no residual raw material. Water (50 mL) was added to the reaction solution, and dichloromethane was extracted (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain 49 (550 mg, yield 90%). MS m / z (ESI): 549.2 [M+1]

[0582] Synthesis of intermediate 49b:

[0583] 49a (550 mg, 1.00 mmol) was dissolved in methanol (25 mL), and then NiCl2·6H2O (15 mg, 0.10 mmol) and NaBH4 (266 mg, 7.00 mmol) were added at 0°C. The whole system was stirred at room temperature for 1.5 h. TLC monitoring showed that there was no residual raw material. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol = 30: 1-20: 1) to obtain 49b (300 mg, yield 54%). MS m / z (ESI): 553.2 [M+1]

[0584] Synthesis of intermediate 49c:

[0585] 49b (300 mg, 0.54 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of acetic anhydride (110 mg, 1.08 mmol) and triethylamine (110 mg, 1.08 mmol), and the whole system was stirred at room temperature for 1 h. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution, and dichloromethane was extracted (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-1: 1) to obtain 49c (250 mg, yield 78%). MS m / z (ESI): 595.2 [M+1]

[0586] Synthesis of final product 49:

[0587] 49c (250 mg, 0.42 mmol) was dissolved in dichloromethane (25 mL), followed by the addition of trifluoroacetic acid (3 mL), and the whole system was stirred at room temperature for 1 h. TLC monitoring showed that there was no residual raw material. Saturated sodium bicarbonate aqueous solution (25 mL) was added to the reaction solution, and dichloromethane was used for extraction (25 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was purified by preparative plate (dichloromethane: methanol = 15: 1) to obtain the final product 49 (100 mg, yield 50%). MS m / z (ESI): 495.2 [M+1]

[0588] 1 H NMR (600MHz, DMSO-d6) δ7.93 (s, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.30-7.25 (m, 2H), 7.21 (dd, J = 6.0Hz, J = 4.8Hz, 1H), 4.0 0(d,J=5.4Hz,2H),3.96(s,2H),3.71(t,J=7.2Hz,2H),3.54(s,3H),3.40(s,1H),2.58-2.55(m,5H),2.37(s,3H),1.78(s,3H),1.71(s,3H).

[0589] Embodiment 50:

[0590]

[0591] Synthesis of intermediate 50a:

[0592] 16a (700 mg, 2.44 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of 29e (0.85 g, 2.92 mmol) and potassium carbonate (1.01 g, 7.31 mmol). The whole system was stirred at 60 ° C and reacted for 24 h. TLC monitoring was performed until no raw material remained. Water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was separated and purified (dichloromethane: methanol = 20: 1-10: 1) to obtain 50a (825 mg, yield 70%). MS m / z (ESI): 482.2 [M+1]

[0593] Synthesis of final product 50:

[0594] 50a (500 mg, 1.09 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and then lithium aluminum hydride (207 mg, 5.45 mmol) was added under ice bath. The whole system was stirred under ice bath for 20 min, and TLC monitoring was followed until no raw material remained. 10% sodium hydroxide aqueous solution (50 mL) was added to the system, and ethyl acetate was extracted (50 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The final product 50 (350 mg, yield 77%) was obtained. MS m / z (ESI): 440.2 [M+1]

[0595] 1 HNMR(600MHz, DMSO-d6)δ8.00-7.99(m,2H),7.64(s,1H),7.50-7.48(m,1H),7.30-7.22(m,2H),7.21-7.18(m,1H),4.75-4.27(br s,1H),4.19(s,2H),3.98(s,2H),3.81-3.78(t,J=7.8Hz,2H),3.52(s,3H),2.63-2.60(t,J=7.8Hz,2H),2.50(s,3H),1.78(s,3H).

[0596] Embodiment 51:

[0597]

[0598] Synthesis of intermediate 51a:

[0599] 1a (2.00 g, 8.29 mmol) was dissolved in 1,4-dioxane (20 mL), followed by addition of pinacol diboron (3.16 g, 12.44 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (330 mg, 0.42 mmol) and potassium acetate (2.44 g, 24.87 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere. The entire system was stirred at 100 ° C for 4 h, and TLC detected that there was no residual raw material. The reaction was directly purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain 51a (2.10 g, yield 88%). MS m / z (ESI): 289.1 [M+1]

[0600] Synthesis of intermediate 51b:

[0601] 2-Bromo-4,6-difluorophenol (300 mg, 1.44 mmol), 29d (275 mg, 1.30 mmol), triphenylphosphine (561 mg, 2.16 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), replaced with nitrogen three times, so that the whole system was in a nitrogen atmosphere, and then diisopropyl azodicarboxylate (437 mg, 2.16 mmol) was added under an ice bath, and the reaction was moved to room temperature for 1 h after the addition was completed. TLC detected that there was no residual raw material. The reaction was directly purified by column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain 51b (550 mg, yield 95%). MS m / z (ESI): 402.0 [M+1]

[0602] Synthesis of intermediate 51c:

[0603] 51a (566 mg, 1.97 mmol) was dissolved in 1,4-dioxane (25 mL), followed by the addition of 51b (610 mg, 1.51 mmol), tetrakistriphenylphosphine palladium (87 mg, 0.08 mmol) and K3PO4·3H2O (805 mg, 3.02 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere. The entire system was stirred at room temperature at 110°C for 4 h, and TLC detected that there was no residual raw material. The reaction was directly purified by column chromatography (dichloromethane: methanol = 20:1) to obtain 51c (575 mg, yield 78%). MS m / z (ESI): 485.1 [M+1]

[0604] Synthesis of intermediate 51d:

[0605] 51c (575 mg, 1.18 mmol) was dissolved in methanol (10 mL), followed by the addition of methylamine hydrochloride (242 mg, 3.56 mmol) and triethylamine (494 mg, 3.56 mmol), and the whole system was stirred at room temperature for 2 h, followed by the addition of sodium borohydride (90 mg, 2.37 mmol), and the whole system was stirred at room temperature for 2 h. TLC detected that there was no residual raw material. Ice water (100 mL) was added to the reaction solution, the pH was adjusted to 1-2 with hydrochloric acid, ethyl acetate (50 mL) was added, and petroleum ether was extracted (50 mL), the organic phase was discarded, the aqueous phase was adjusted to pH 8-9 with sodium bicarbonate, and ethyl acetate was extracted (80 mL×2), the organic phases were combined, washed with saturated sodium chloride (100 mL×2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain 51d (84 mg, yield 14%). MS m / z(ESI):500.2[M+1]

[0606] Synthesis of final product 51:

[0607] 51d (84 mg, 0.17 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and then lithium aluminum hydride (13 mg, 0.34 mmol) was added under ice bath. The whole system was stirred under ice bath for 20 min, and TLC monitoring was followed until there was no raw material left. The system was added to 10% sodium hydroxide (50 mL) on ice, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 10: 1-5: 1) to obtain the final product 51 (50 mg, yield 65%). MS m / z (ESI): 458.2 [M+1]

[0608] 1 H NMR (600MHz, DMSO-d6) δ8.08-8.01(m,2H),7.71(s,1H),7.53-7.52(m,1H),7.38-7.34(m,1H),7.22-7.19(m,1H),4.17 (s,2H),4.03(s,2H),3.74-3.72(t,J=7.2Hz,2H),3.51(s,3H),2.60-2.58(t,J=7.2Hz,2H),2.40(s,3H),1.77(s,3H).

[0609] Embodiment 52:

[0610]

[0611] Synthesis of intermediate 52a:

[0612] 50a (500 mg, 1.04 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of di-tert-butyl dicarbonate (340 mg, 3.12 mmol), triethylamine (433 mg, 3.12 mmol), and a catalytic amount of 4-dimethylaminopyridine. The system was stirred at room temperature for 3 h. TLC monitoring revealed that no raw material remained. The reaction was directly separated and purified by column chromatography (dichloromethane: methanol = 50: 1) to obtain 52a (539 mg, yield 89%). MS m / z (ESI): 582.2 [M+1]

[0613] Synthesis of intermediate 52b:

[0614] 52a (520 mg, 0.89 mmol) was dissolved in ethanol (5 mL), and then a solution of sodium hydroxide (143 mg, 3.58 mmol) dissolved in ethanol (2.5 mL) was added. The whole system was stirred at room temperature for 5 h. TLC showed that there was no residual raw material. Water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL). The organic phase was discarded, and the aqueous phase was adjusted to pH 1-2 with hydrochloric acid, and ethyl acetate was extracted (50 mL×3). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain 52b (460 mg, yield 96%). MS m / z (ESI): 552.2 [M-1]

[0615] Synthesis of intermediate 52c:

[0616] 52b (94 mg, 0.17 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of dimethylamine hydrochloride (28 mg, 0.34 mmol), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate (129 mg, 0.34 mmol) and N,N-diisopropylethylamine (112 uL, 0.68 mmol). The whole system was stirred at room temperature for 5 h. TLC showed that there was no residual raw material. Water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. 52c (60 mg, yield 61%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-20: 1). MS m / z (ESI): 581.2 [M+1]

[0617] Synthesis of final product 52:

[0618] 52c (60 mg, 0.10 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of 2 mL of trifluoroacetic acid. The whole system was stirred at room temperature for 2 h, and TLC monitoring was performed until no raw material remained. Water (50 mL) was added to the reaction solution, and the pH was adjusted to 8-9 with sodium bicarbonate. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-5: 1) to obtain the final product 52 (15 mg, yield 37%). MS m / z (ESI): 466.1 [M+1]

[0619] 1H NMR (600MHz, DMSO-d6) δ8.01-7.98(m,2H),7.73(s,1H),7.49-7.47(m,1H),7.29-7.26(m,2H),7.21-7.18(s,1H),4.08(s,2H),3.98 (s,2H),3.83-3.81(t,J=6.6Hz,2H),3.61(s,3H),2.92(s,3H),2.85(s,3H),2.67-2.52(t,J=6.6Hz,2H),2.43(s,3H),1.87(s,3H).

[0620] Embodiment 53:

[0621]

[0622] Synthesis of intermediate 53a:

[0623] 5-Bromobenzo[B]thiophene-3-carboxylic acid (1.00 g, 3.87 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of deuterated dimethylamine hydrochloride (0.40 g, 4.65 mmol), HATU (1.76 g, 4.65 mmol) and N,N-diisopropylethylamine (1.05 g, 7.74 mmol). The whole system was stirred at room temperature overnight, and TLC monitoring showed that there was no residual raw material. Water (100 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 1a (0.90 g, yield 80%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-20: 1). MS m / z (ESI): 292.0 [M+1]

[0624] Synthesis of intermediate 53b:

[0625] 53a (0.90 g, 3.08 mmol) was dissolved in ethylene glycol dimethyl ether (30 mL), followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (0.57 g, 3.69 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.252 g, 0.31 mmol) and potassium carbonate (1.27 g, 9.24 mmol), and replaced with nitrogen three times to place the entire system under a nitrogen atmosphere. The system was refluxed and stirred at 80°C for 4 h, and no raw material remained after TLC monitoring. The mixture was concentrated under reduced pressure and purified by column chromatography (dichloromethane: methanol = 50: 1-10: 1) to obtain 1b (0.80 g, yield 81%). MS m / z (ESI): 322.1 [M+1]

[0626] Synthesis of intermediate 53c:

[0627] 53b (0.80 g, 2.49 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and then deuterated lithium aluminum tetrahydride (0.21 g, 4.98 mmol) was added under ice-water bath. The whole system was stirred at room temperature overnight and detected by TLC until no raw material remained. Water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 1c (0.65 g, yield 84%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-15: 1). MS m / z (ESI): 310.1 [M+1]

[0628] Synthesis of intermediate 53d:

[0629] 53c (0.650 g, 2.10 mmol) was dissolved in N,N-dimethylformamide (30 mL), followed by the addition of 29e (0.73 g, 2.52 mmol) and anhydrous potassium carbonate (0.58 g, 4.20 mmol). The whole system was stirred at room temperature overnight. TLC monitoring showed that no raw material remained. 100 mL of water was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 1d (0.72 g, yield 69%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 50: 1-20: 1). MS m / z (ESI): 504.25 [M+1]

[0630] Synthesis of final product 53:

[0631] 53d (0.12 g, 0.24 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and then lithium aluminum tetrahydride (0.02 g, 0.48 mmol) was added under ice-water bath. The whole system was stirred at room temperature overnight and detected by TLC until no raw material remained. Water (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 53 (0.08 g, yield 73%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 100: 1-15: 1). MS m / z (ESI): 462.24 [M+1]

[0632] 1H NMR (600MHz, CDCl3) δ7.87-7.83 (m, 2H), 7.45-7.43 (d, J = 8.4Hz 1H),7.24(s,1H),7.12-7.10(m,3H),4.25(s,2H),3.77-3.75(t,J=7.2Hz,2H),3.55(s,3H),2.63-2.61(t,J=6.6Hz,2H),1.84(s,3H).

[0633] Embodiment 54:

[0634]

[0635] Synthesis of intermediate A':

[0636] 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (0.77 g, 4.99 mmol) and triethylamine (1.01 g, 9.99 mmol) were added to 20 mL of dichloromethane, followed by 4-toluenesulfonyl chloride (1.43 g, 7.49 mmol), and the mixture was reacted at room temperature for 4 h. The reaction was complete after TLC monitoring. 20 mL of water was added to the system, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain intermediate A' (1.07 g, 73%). MS m / z (ESI): 293.1 [M+1]

[0637] Synthesis of intermediate 1a':

[0638] Dissolve 4-bromo-2-methylaminoaniline (2.00 g, 9.94 mmol) in 50 mL of tetrahydrofuran, then add carbonyldiimidazole (2.40 g, 14.9 mmol), stir the system overnight at room temperature, and monitor by TLC until no raw material remains. The reaction is directly separated and purified by column chromatography (dichloromethane: methanol = 30:1) to obtain 1a' (0.76 g, yield 34%). MS m / z (ESI): 226.9 [M+1]

[0639] Synthesis of intermediate 1b':

[0640] 1a' (0.76 g, 3.34 mmol) was dissolved in 15 mL N, N-dimethylformamide, followed by the addition of 2-chloroethyldimethylamine (669 mg, 6.68 mmol), potassium carbonate (924 mg, 10.02 mmol) and sodium iodide (502 mg, 3.34 mmol). The whole system was stirred at 50 ° C for 8 h, and TLC monitoring was performed until no raw material remained. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. 1b' (0.39 g, yield 39%) was obtained by column chromatography separation and purification (ethyl acetate: methanol = 30: 1). MS m / z (ESI): 298.0 [M+1]

[0641] Synthesis of intermediate 1c':

[0642] 1b' (160 mg, 0.54 mmol) was dissolved in 15 mL 1,4-dioxane, followed by the addition of 2-methoxy-3,4-fluoro-phenylboronic acid (126 mg, 0.80 mmol), tetrakistriphenylphosphine palladium (31 mg, 0.03 mmol) and potassium phosphate trihydrate (215 mg, 0.80 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere. The entire system was stirred at room temperature at 100 ° C for 4 h, and TLC monitoring and tracking was performed until no raw material remained. The reaction was directly purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 1c' (174 mg, yield 90%). MS m / z (ESI): 362.1 [M+1]

[0643] Synthesis of intermediate 1d':

[0644] 1c' (74 mg, 0.21 mmol) was dissolved in 5 mL of dichloromethane, and then boron tribromide (160 mg, 0.63 mmol) was slowly added dropwise under an ice bath. The whole system was stirred at room temperature and reacted for 4 h. TLC monitoring and tracking was performed until no raw material remained. 20 mL of water was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 40: 1-20: 1) to obtain 1d' (30 mg, yield 42%). MS m / z (ESI): 348.1 [M+1]

[0645] Synthesis of the final product (Compound 1'):

[0646] 1c (30 mg, 0.086 mmol) was dissolved in 5 mL N, N-dimethylformamide, followed by the addition of intermediate A' (30 mg, 0.086 mmol) and potassium carbonate (24 mg, 0.173 mmol), the whole system was stirred at 50 ° C, reacted for 4 h, and monitored by TLC until no raw material remained. 30 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 40: 1-20: 1) to obtain the final product 1' (37 mg, yield 90%). MS m / z (ESI): 484.2 [M+1]

[0647] 1 H NMR (600MHz, CDCl3) δ7.28 (s, 1H), δ7.22 (d, J = 8.4Hz, 1H), δ7.10-7.08 (m, 1H), δ7.03 (d, J = 8.4Hz, 1H), δ6.76 (s, 1 H), δ4.08-4.05 (m, 4H), δ3.73 (s, 3H), δ2.90 (t, J = 7.2Hz, 2H), δ2.70 (t, J = 6.6Hz, 2H), δ2.36 (s, 6H), δ2.25 (s, 6H).

[0648] Embodiment 55:

[0649]

[0650] Synthesis of intermediate 2a':

[0651] 1b' (160 mg, 0.54 mmol) was dissolved in 15 mL of 1,4-dioxane, followed by the addition of 3-fluoro-2-hydroxyphenylboronic acid (126 mg, 0.81 mmol), tetrakistriphenylphosphine palladium (31 mg, 0.03 mmol) and potassium phosphate trihydrate (215 mg, 0.81 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere. The entire system was stirred at room temperature at 100 ° C for 4 h, and TLC monitoring and tracking was performed until no raw material remained. The reaction was directly purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 2a' (157 mg, yield 89%). MS m / z (ESI): 330.2 [M+1]

[0652] Synthesis of the final product (Compound 2'):

[0653] 2a' (100 mg, 0.30 mmol) was dissolved in 5 mL N, N-dimethylformamide, followed by the addition of A' (64 mg, 0.30 mmol) and potassium carbonate (63 mg, 0.46 mmol), the whole system was stirred at 50 ° C, reacted for 4 h, and monitored by TLC until no raw material remained. 30 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 40: 1-20: 1) to obtain the final product 2' (50 mg, yield 35%). MS m / z (ESI): 466.1 [M+1]

[0654] 1 H NMR (600MHz, DMSO-d6) δ7.31 (s, 1H), δ7.25-7.22 (m, 1H), δ7.20-7.15 (m, 4H), δ3.95-3.90 (m, 2H), δ3.63-3.6 0(m,2H),δ3.52(s,3H),δ3.39(s,2H),δ3.38(s,3H),δ2.62(s,2H),δ2.20(s,6H),δ1.90(s,3H),δ1.76(s,3H).

[0655] Embodiment 56:

[0656]

[0657] Synthesis of intermediate 3a':

[0658] 5-Bromo-2-benzoxazolone (1.70 g, 8.0 mmol) was dissolved in 30 mL N,N-dimethylformamide, and then dimethylaminochloroethane hydrochloride (1.40 g, 9.6 mmol) and potassium carbonate (3.30 g, 2.4 mmol) were added under ice bath, and stirred at 125°C for 4 h. After the reaction, 100 mL of water was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was separated and purified (dichloromethane: methanol = 50: 1-15: 1) to obtain 3a' (1.70 g, yield 64%). MS m / z (ESI): 285.0 [M+1]

[0659] Synthesis of intermediate 3b':

[0660] 3a' (600 mg, 2.1 mmol) was dissolved in 20 mL of dioxane and 4 mL of water, and then 3,4-difluoro-2-methoxyphenylboronic acid (595 mg, 3.15 mmol) and tetrakistriphenylphosphine palladium (122 mg, 0.11 mmol) and potassium phosphate trihydrate (838 mg, 3.15 mmol) were added, and the mixture was stirred at 100°C for 4 h. After the reaction, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 3b' (250 mg, yield 34%) was obtained. MS m / z (ESI): 349.1 [M+1]

[0661] Synthesis of intermediate 3c':

[0662] 3b' (250 mg, 0.72 mmol) was dissolved in 20 mL of dichloromethane, and then boron tribromide (375 mg, 1.44 mmol) was slowly added dropwise under an ice-water bath, and stirred at room temperature overnight. After the reaction was completed, 30 mL of water was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was separated and purified (dichloromethane: methanol = 50: 1-10: 1) to obtain 3c' (200 mg, yield 83%). MS m / z (ESI): 335.1 [M+1]

[0663] Synthesis of the final product (Compound 3'):

[0664] 3c' (200 mg, 0.60 mmol) was dissolved in 15 mL N, N-dimethylformamide, and then intermediate A' (184 mg, 0.60 mmol) and potassium carbonate (165 mg, 1.2 mmol) were added, and the reaction was stirred at 50 ° C for 3 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography separation and purification (dichloromethane: methanol = 50: 1-10: 1) was performed to obtain 3' (135 mg, yield 48%). MS m / z (ESI): 471.2 [M+1]

[0665] 1HNMR (600MHz, CDCl3) δ7.26 (s, 1H), 7.24-7.19 (m, 2H), 7.09-7.06 (m, 1H), 6.77-6.74 (m, 1H), 4.07 (t, J = 7. 2Hz,2H),4.00(s,2H),3.73(s,3H),2.90(t,J=6.6Hz,2H),2.75(s,2H),2.37(s,6H),2.25(d,J=3.0Hz,6H).

[0666] Embodiment 57:

[0667]

[0668] Synthesis of intermediate 4a':

[0669] 3a' (600 mg, 2.10 mmol) was dissolved in 20 mL of dioxane and 4 mL of water, and then 3-fluoro-2-hydroxyphenylboronic acid (494 mg, 3.15 mmol) and tetrakistriphenylphosphine palladium (122 mg, 0.11 mmol) and potassium phosphate trihydrate (843 mg, 3.15 mmol) were added, and the mixture was stirred at 100 °C for 4 h. After the reaction, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 4a' (400 mg, yield 60%) was obtained. MS m / z (ESI): 317.1 [M+1]

[0670] Synthesis of the final product (Compound 4'):

[0671] 4a' (150 mg, 0.47 mmol) was dissolved in 10 mL N,N-dimethylformamide, and then intermediate A' (146 mg, 0.47 mmol) and anhydrous potassium carbonate (130 mg, 0.94 mmol) were added, and the reaction was stirred at 50°C for 3 h. After the reaction was completed, 30 mL of water was added to the reaction solution, and ethyl acetate was extracted (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Column chromatography was separated and purified (dichloromethane: methanol = 50: 1-10: 1) to obtain 4' (145 mg, yield 68%). MS m / z (ESI): 453.2 [M+1]

[0672] 1HNMR (600MHz, CDCl3) δ7.21(s,2H),7.19(s,1H),7.14-7.19(m,3H),3.97(t,J=6.0Hz,2H),3.74(t,J =7.8Hz,2H),3.63(s,3H),2.73(s,2H),2.61(t,J=7.2Hz,2H),2.33(s,6H),2.02(s,3H),1.95(s,3H).

[0673] Embodiment 58:

[0674]

[0675] Synthesis of intermediate 5a':

[0676] 1b' (160 mg, 0.54 mmol) was dissolved in 15 mL 1,4-dioxane, followed by the addition of 4-fluoro-2-hydroxyphenylboronic acid (126 mg, 0.81 mmol), tetrakistriphenylphosphine palladium (31 mg, 0.03 mmol) and potassium phosphate trihydrate (215 mg, 0.81 mmol), replaced with nitrogen three times, and the entire system was placed under a nitrogen atmosphere, stirred at 100 ° C for 4 h, and monitored by TLC until no raw material remained. The reaction was directly purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 5a' (157 mg, yield 89%). MS m / z (ESI): 330.2 [M+1]

[0677] Synthesis of the final product (Compound 5'):

[0678] 5a' (100 mg, 0.30 mmol) was dissolved in 10 mL N, N-dimethylformamide, followed by the addition of intermediate A' (64 mg, 0.30 mmol) and potassium carbonate (63 mg, 0.46 mmol), and the reaction was stirred at 50 ° C for 4 h, and TLC monitoring was performed until no raw material remained. 30 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The final product 5' (72 mg, yield 51%) was obtained. MS m / z (ESI): 466.1 [M+1]

[0679] 1H NMR (600MHz, CDCl3) δ7.28 (s, 1H), δ7.17 (s, 2H), δ7.01 (d, J = 8.4Hz, 1H), δ6.75-6.73 (m, 1H), δ6.67 (d, J = 10.8Hz, 1H), δ4.13 ( s,2H), δ3.94(t,J=7.2Hz,2H), δ3.67(s,3H), δ3.47(s,3H), δ2.77(t,J=7.8Hz,2H), δ2.36(s,6H), δ2.10(s,3H), δ1.99(s,3H).

[0680] Embodiment 59:

[0681]

[0682] Synthesis of intermediate 6a':

[0683] 2-Fluoro-4-bromonitrobenzene (5.00 g, 22.7 mmol) was dissolved in 50 mL of N,N-dimethylformamide, and methylamine (1.41 g, 45.4 mmol) and potassium carbonate (3.14 g, 22.7 mmol) were added. The system was reacted at room temperature for 12 h under nitrogen protection. TLC monitoring showed that the reaction was complete. 200 mL of water was added to the reaction solution and stirred for ten minutes. After filtration, the solid was collected and dried in a vacuum oven to obtain intermediate 6a' (5.03 g, yield 96%). MS m / z (ESI): 231.1 [M+1]

[0684] Synthesis of intermediate 6b':

[0685] Intermediate 6a' (5.03 g, 21.7 mmol) was dissolved in anhydrous ethanol (100 mL) and water (50 mL), and zinc powder (7.12 g, 108.8 mmol) and ammonium chloride (11.6 g, 217.7 mmol) were added in batches. The system was reacted at 70 ° C for 4 h, during which the color of the system changed from yellow to colorless. TLC monitoring showed that the reaction was complete. After filtering the system, the filtrate was concentrated and the organic solvent was removed. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain intermediate 6b' (4.70 g, crude product). The product was not further purified and was directly used in the next step. MS m / z (ESI): 201.1 [M+1]

[0686] Synthesis of intermediate 6c':

[0687] The intermediate 6b' (2.00 g, 9.9 mmol) was dissolved in 20 mL of dichloromethane, and carbonyldiimidazole (1.77 g, 10.9 mmol) was added at once. The reaction was carried out at room temperature under nitrogen protection for 1 h. The system turned brown. Liquid quality monitoring showed that the raw material was completely consumed. The system was filtered, the solid was collected, and vacuum dried to obtain the intermediate 6c' (1.50 g, yield 66%). The product was not further purified and was directly used in the next step. MS m / z (ESI): 227.1 [M+1]

[0688] Synthesis of intermediate 6d':

[0689] The intermediate 6c' (1.50g, 6.6mmol) was dissolved in 20mL N,N-dimethylformamide, sodium hydride (792mg, 19.8mmol, 60%) was added at 0℃, and dimethylaminochloroethane hydrochloride (1.50g, 9.9mmol) was added after stirring the system for 10 minutes. Then the reaction was carried out at room temperature for 5 hours. TLC monitoring showed that the reaction was complete and the target mass spectrum was formed. 70mL of water was added to the reaction solution, and after stirring for 3 minutes, ethyl acetate was extracted (30mL×3). The organic phases were combined, washed with saturated sodium chloride (20mL x 2), and the organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the crude product was separated by column chromatography (ethyl acetate: methanol: ammonia water = 20:1:0.05-5:1:0.05), the product fractions were collected, combined and concentrated to obtain the intermediate 6d' (1.10g, yield 56%). MS m / z (ESI): 298.2 [M+1]

[0690] Synthesis of intermediate 6e':

[0691] The intermediate 6d' (0.30 g, 1.0 mmol) and 5-fluoro-2-hydroxyphenylboronic acid (235 mg, 1.5 mmol) were dissolved in dioxane (3 mL) and water (0.3 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (73 mg, 0.1 mmol) and potassium carbonate (278 mg, 2 mmol) were added. The system was reacted at 100 ° C for 10 h under nitrogen protection. The liquid quality showed that the reaction was complete. After cooling, the system was filtered, the filtrate was concentrated, and ethyl acetate (30 mL) and water (30 mL) were added. After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with saturated sodium chloride (20 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was separated and purified by thin plate chromatography (ethyl acetate: methanol = 5:1) to obtain intermediate 6e' (60 mg, yield 18%). MS m / z(ESI):330.1[M+1]

[0692] Synthesis of the final product (Compound 6'):

[0693] The intermediate 6e' (0.06g, 0.18mmol) and 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (28mg, 0.18mmol) were dissolved in 5mL tetrahydrofuran, and tributylphosphine (73.71mg, 0.36mmol) and diazolidinone (92mg, 0.36mmol) were added at 0°C. The system was reacted at room temperature for 12h under nitrogen protection. Liquid quality monitoring showed that the reaction was complete. After filtering the system, the filtrate was concentrated. Column chromatography separation and purification (dichloromethane: methanol = 40:1-20:1) gave the final product 6' (41mg, yield 46%). MS m / z (ESI): 466.2 [M+1]

[0694] 1 H NMR (600MHz, CDCl3) δ7.24-7.18(m,2H),7.09-7.03(m,1H),7.03-6.93(m,2H),6.91-6.83( m,1H),4.11-3.97(m,2H),3.92-3.84(m,2H),3.69-3.61(m,3H),3.50-3.43(m,3H),2.68(br s,4H),2.43-2.26(m,6H),2.12-2.04(m,3H),2.03-1.94(m,3H).

[0695] Embodiment 60:

[0696]

[0697] Synthesis of intermediate 7a':

[0698] The intermediate 6d' (0.30g, 1.0mmol) and 3-chloro-2-hydroxyphenylboronic acid (260mg, 1.5mmol) were dissolved in dioxane (3mL) and water (0.3mL), and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (73mg, 0.1mmol) and potassium carbonate (278mg, 2mmol) were added. The system was reacted at 100℃ for 10h under nitrogen protection. The liquid quality showed that the reaction was complete. After cooling, the system was filtered, the filtrate was concentrated, and ethyl acetate (30mL) and water (30mL) were added. After separation, the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, washed with saturated sodium chloride (20mL×2), dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was separated by thin plate chromatography (ethyl acetate: methanol = 5:1) to obtain intermediate 7a' (0.20g, yield 58%). MS m / z(ESI):345.8[M+1]

[0699] Synthesis of the final product (Compound 7'):

[0700] The intermediate 7a' (0.03g, 0.087mmol) and 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (26mg, 0.17mmol) were dissolved in 5mL tetrahydrofuran, and triphenylphosphine (45mg, 0.17mmol) and diisopropyl azodicarboxylate (35mg, 0.17mmol) were added at 0°C. The system was reacted at room temperature for 12h under nitrogen protection. Liquid quality monitoring showed that the reaction was complete. After filtering the system, the filtrate was concentrated. Column chromatography separation and purification (dichloromethane: methanol = 40:1-20:1) gave the final product 7' (21mg, yield 47%). MS m / z (ESI): 482.0 [M+1]

[0701] 1 H NMR (600MHz, CDCl3) δ7.39-7.38(m,1H),7.37-7.25(m,3H),7.15-7.09(m,1H),6.99(d,J=8.82Hz,1H),4.06 -4.03(m,2H),3.61(s,3H),3.51-3.45(m,5H),2.78-2.67(m,2H),2.62-2.55(m,2H),1.92(d,J=5.95Hz,6H).

[0702] Example 61:

[0703]

[0704] Synthesis of intermediate 8a':

[0705] 2-Bromo-6-fluorophenol (10.0 g, 52.3 mmol), 2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanol (16.2 g, 104.7 mmol) and triphenylphosphine (27.5 g, 104.7 mmol) were dissolved in 70 mL of tetrahydrofuran. Under nitrogen protection, diisopropyl azodicarboxylate (21.2 g, 104.7 mmol) was added at 0°C. The system was reacted at room temperature for 12 h, and TLC monitoring showed that the reaction was complete. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride (30 mL x 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate 8a' (12.0 g, yield 70%).

[0706] MS m / z(ESI):327.2[M+1]

[0707] Synthesis of intermediate 8b':

[0708] The intermediate 8a' (2.00 g, 6.1 mmol) and bispinacol borate (4.66 g, 18.3 mmol) were dissolved in 30 mL of ethylene glycol dimethyl ether, and potassium acetate (1.80 g, 18.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (357.8 mg, 0.49 mmol) were added. The system was placed under nitrogen protection and reacted at 100 ° C for 12 h. TLC monitoring showed that the reaction was complete. 50 mL of water was added to the system, and dichloromethane was extracted (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate 8b' (2.00 g, yield 61%). MS m / z (ESI): 375.2 [M+1]

[0709] Synthesis of intermediate 8c':

[0710] 2-Fluoro-4-bromonitrobenzene (2.00 g, 9.1 mmol) was dissolved in 40 mL N,N-dimethylformamide, followed by the addition of N,N-dimethylethylenediamine (1.00 g, 11.3 mmol) and triethylamine (1.40 g, 13.6 mmol). The whole system was stirred at room temperature for 2.5 h. TLC showed that there was no residual raw material. 100 mL of water was added to the reaction solution, and ethyl acetate was extracted (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (50 mL × 2), and dried over anhydrous sodium sulfate to obtain 8c' (2.50 g, yield 96%). MS m / z (ESI): 288.0 [M+1]

[0711] Synthesis of intermediate 8d':

[0712] 8c' (2.50 g, 8.7 mmol) was dissolved in 60 mL of ethanol-water mixed solution (ethanol: water = 5: 1), followed by addition of iron powder (1.26 g, 22.5 mmol) and 6 mL of saturated ammonium chloride solution. The whole system was refluxed at 80 ° C and TLC was detected until there was no raw material left. After the reaction system was cooled to room temperature, it was filtered through diatomaceous earth. The diatomaceous earth was rinsed with 50 mL of ethyl acetate, all the filtrate was collected, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (dichloromethane: methanol = 20: 1-10: 1) to obtain 8d' (2.00 g, yield 89%). MS m / z (ESI): 258.0 [M+1]

[0713] Synthesis of intermediate 8e':

[0714] Dissolve the intermediate 8d' (20.0 g, 77.5 mmol) in 210 mL of dichloromethane and add carbonyldiimidazole (13.8 g, 85.2 mmol). The system was reacted at room temperature for 12 h. TLC monitoring showed that the reaction was complete. Add 100 mL of water to the system, extract with dichloromethane (100 mL × 3), combine the organic phases, wash with saturated brine, and concentrate the organic phase. The crude product was slurried with methyl tert-butyl ether (50 mL), filtered and dried to obtain the intermediate 8e' (15.0 g, yield 68%). MS m / z (ESI): 284.2 [M+1]

[0715] Synthesis of the final product (Compound 8'):

[0716] Intermediate 8e' (1.00 g, 3.52 mmol) and intermediate 8b' (1.58 g, 4.22 mmol) were dissolved in dioxane (15 mL) and water (3 mL), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (206 mg, 0.28 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were added. The system was reacted at 100 ° C for 12 h under nitrogen protection. Liquid chromatography showed that the reaction was complete. After filtering and concentrating the system, column chromatography separation and purification (dichloromethane: methanol = 20: 1-15: 1) was performed to obtain the final product 8' (0.80 g, yield 50%). MS m / z (ESI): 452.2 [M+1]

[0717] 1 H NMR (600MHz, CD3OD) δ7.23(s,1H),7.14-7.11(m,4H),7.05-7.03(m,1H),4.02(t,J=6.8Hz,2H),3.70(t,J=7 .2Hz,2H),3.56(s,3H),2.70(t,J=7.2Hz,2H),2.60(t,J=6.8Hz,2H),2.32(s,6H),1.94(s,3H),1.91(s,3H).

[0718] Embodiment 62:

[0719]

[0720] Synthesis of intermediate 9a':

[0721] Dissolve N-Boc-4-hydroxypiperidine (0.30 g, 1.49 mmol) in 5 mL of dichloromethane, then add triethylamine (226.3 mg, 2.24 mmol), then slowly add methylsulfonyl chloride (205 mg, 1.79 mmol) in an ice bath, and the system reacts at room temperature for 2 h, and TLC monitoring and tracking is performed until there is no raw material left. Add 10 mL of water to the reaction solution, extract with dichloromethane (10 mL × 3), combine the organic phases, wash with saturated sodium chloride (10 mL × 2), dry with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain intermediate 9a' (416 mg, yield 100%). MS m / z (ESI): 280.1 [M+1]

[0722] Synthesis of intermediate 9b':

[0723] Compound 8 (0.10 g, 0.22 mmol) was dissolved in 2 mL N, N-dimethylformamide, sodium hydrogen (18 mg, 0.44 mmol, 60% content) was slowly added under ice bath, stirred for 5 mins, then intermediate 9a' was added to the reaction solution, stirred for 2 h at room temperature, and monitored by TLC until no raw material remained. 10 mL of saturated aqueous ammonium chloride solution was added to the system, extracted with dichloromethane (5 mL × 3), the organic phases were combined, washed with saturated sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 9b' (0.30 g, crude product), which was directly used in the next step.

[0724] Synthesis of the final product (Compound 9'):

[0725] The intermediate 9b' (0.30 g, crude product) was dissolved in 5 mL of dichloromethane, followed by the addition of 1 mL of trifluoroacetic acid. The system was reacted at room temperature for 12 h, and TLC monitoring was performed until no raw material remained. The solvent was removed under reduced pressure, and column chromatography was performed for separation and purification (dichloromethane: methanol = 40:1-20:1) to obtain the final product 9' (20 mg, 2-step yield 17%). MS m / z (ESI): 535.3 [M+1]

[0726] 1H NMR (600MHz, CDCl3) δ7.60-7.56(m,1H),7.30(d,J=8.4Hz,1H),7.24(d,J=1.6Hz,1H),7.21-7.1 0(m,3H),4.39-4.28(m,1H),3.92(t,J=6.8Hz,2H),3.65(t,J=7.6Hz,2H),3.52(s,3H),3.17(br d,J=10.8Hz,2H),2.77-2.67(m,2H),2.69-2.67(m,2H),2.62-2.60(m,2H),2.58-2.47(m,2H),2.31(s,6H),1.94(s,3H),1.89(s,5H).

[0727] Embodiment 63:

[0728]

[0729] Synthesis of intermediate 10a':

[0730] 5-Bromo-1,3-dihydrobenzimidazol-2-one (1.00 g, 4.7 mmol) was dissolved in 10 mL N,N-dimethylformamide, and sodium hydride (1.50 g, 37.6 mmol, 60% content) and 2-chloroethyldimethylamine hydrochloride (2.70 g, 18.8 mmol) were slowly added under ice bath, and the reaction was stirred at room temperature for 10 h. TLC monitoring and tracking was performed until no raw material remained. 30 mL of saturated aqueous ammonium chloride solution was added to the system, and dichloromethane was extracted (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride (15 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 10a' (0.50 g, yield 22%) was obtained. MS m / z (ESI): 355.1 [M+1]

[0731] Synthesis of the final product (Compound 10'):

[0732] The intermediate 10a' (0.15g, 0.42mmol) was dissolved in 5mL tetrahydrofuran and 0.5mL water, and then the intermediate 8b' (316mg, 0.84mmol), potassium carbonate (117mg, 0.84mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (31mg, 0.042mmol) were added, and the atmosphere was replaced with nitrogen three times. The whole system was placed under a nitrogen atmosphere, and the reaction was stirred at 100°C for 10h, and TLC monitoring and tracking was performed until there was no raw material left. The solvent was removed under reduced pressure, and the product was directly purified by column chromatography (dichloromethane: methanol = 20:1) to obtain the final product 10' (37mg, yield 16%). MS m / z (ESI): 523.3 [M+1]

[0733] 1 H NMR(600MHz,DMSO-d6)δ7.31-7.11(m,6H),4.09-4.03(m,4H),3.73-3.69(m,2H),3.57(s,3H) ),2.75-2.69(m,4H),2.61-2.57(m,2H),2.35(s,6H),2.31(s,6H),1.95(s,3H),1.92(s,3H).

[0734] Embodiment 64:

[0735]

[0736] Synthesis of intermediate 11a':

[0737] N-Hydroxyethylpiperidine (0.30 g, 2.3 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (352 mg, 3.5 mmol), and then methylsulfonyl chloride (319 mg, 2.8 mmol) was slowly added under an ice bath. The system was reacted at room temperature for 2 h, and TLC monitoring was performed until no raw material remained. The solvent was removed under reduced pressure to obtain intermediate 11a' (481 mg, yield 100%), which was directly used for the next step. MS m / z (ESI): 208.0 [M+1]

[0738] Synthesis of the final product (Compound 11'):

[0739] Compound 8' (0.08 g, 0.17 mmol) was dissolved in 2 mL N, N-dimethylformamide, sodium hydride (14 mg, 0.35 mmol, 60% content) was slowly added under ice bath, stirred for 5 mins, then intermediate 11a' was added to the reaction solution, stirred for 2 h at room temperature, and monitored by TLC until no raw material remained. 10 mL of saturated aqueous ammonium chloride solution was added to the system, extracted with dichloromethane (5 mL × 3), the organic phases were combined, washed with saturated sodium chloride (5 mL × 2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol = 40: 1-20: 1) to obtain the final product 11' (28 mg, yield 27%). MS m / z (ESI): 563.3 [M+1]

[0740] 1 H NMR(600MHz,CD3OD)δ7.30-7.12(m,6H),4.14-4.04(m,4H),3.71(t,J=7.6Hz,2H),3.58(s,3H), 2.73-2.61(m,4H),2.61-2.32(m,6H),2.32(s,6H),1.95(s,3H),1.92(s,3H),1.63-1.45(m,6H).

[0741] Embodiment 65:

[0742]

[0743] Synthesis of intermediate 12a':

[0744] Dissolve bis(trichloromethyl) carbonate (3.45 g, 11.6 mmol) in 70 mL of dichloromethane, then slowly drop a dichloromethane solution of m-bromoaniline and triethylamine (30 mL) under nitrogen atmosphere and ice bath, and react at room temperature for 0.5 h. Then, slowly drop the above liquid into a solution of methoxyamine hydrochloride (2.67 g, 31.9 mmol) and triethylamine (6.47 g, 63.9 mmol) dissolved in N,N-dimethylformamide (70 mL) under nitrogen atmosphere and ice bath, and react at room temperature for 3 h, and monitor by TLC until no raw material remains. Add 200 mL of water to the reaction solution, extract with ethyl acetate (100 mL × 3), combine the organic phases, wash with saturated sodium chloride (30 mL × 2), dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and recrystallize from petroleum ether: ethyl acetate (30 mL: 10 mL) to obtain intermediate 12a' (2.70 g, yield 38%). MS m / z(ESI):244.9[M+1]

[0745] Synthesis of intermediate 12b':

[0746] The intermediate 12a' was dissolved in 50 mL of dichloromethane, and [bis(trifluoroacetyloxy)iodo]benzene (5.70 g, 13.3 mmol) was added at -10°C. The system was reacted at this temperature for 0.5 h, and TLC monitoring was performed until no raw material remained. 50 mL of water was added to the reaction solution, and ethyl acetate was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The intermediate 12b' (0.65 g, yield 26%) was obtained. MS m / z (ESI): 242.9 [M+1]

[0747] Synthesis of intermediate 12c':

[0748] The intermediate 12b' (0.60g, 2.5mmol) was dissolved in 10mL N,N-dimethylformamide. At 0℃, sodium hydrogen (350mg, 60% content) was slowly added. The system was reacted at room temperature for 10h. Then 2-chloroethyldimethylamine (711mg, 5.0mmol) was added to the reaction solution. The system was reacted at room temperature for 3h. TLC monitoring and tracking was performed until no raw material remained. 30mL of water was added to the reaction solution, and ethyl acetate was extracted (15mL×3). The organic phases were combined, washed with saturated sodium chloride (15mL×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain the intermediate 12c' (0.80g), which was directly used for the next step. MS m / z(ESI):314.0[M+1]

[0749] Synthesis of the final product (Compound 12'):

[0750] The intermediate 12c' (0.60 g, 1.9 mmol) was dissolved in 15 mL of tetrahydrofuran and 1.5 mL of water, and then compound 22' (1.43 g, 3.8 mmol), potassium carbonate (528 mg, 3.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (139 mg, 0.19 mmol) were added, and the atmosphere was replaced with nitrogen three times, so that the entire system was placed under a nitrogen atmosphere, and the reaction was stirred at 100 ° C for 10 hours, and TLC monitoring and tracking was performed until there was no raw material left. The solvent was removed under reduced pressure, and the product was directly purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the final product 12' (80 mg, yield 18%). MS m / z (ESI): 482.2 [M+1]

[0751] 1H NMR(600MHz,CD3OD)δ7.30-7.10(m,6H),4.17(s,3H),4.05-4.02(m,2H),3.73-3.70(m,2H) ,3.58(s,3H),2.72-2.68(m,2H),2.62-2.58(m,2H),2.31(s,6H),1.94(s,3H),1.93(s,3H).

[0752] Embodiment 66:

[0753]

[0754] Synthesis of the final product (Compound 13'):

[0755] Compound 8' (0.10 g, 0.22 mmol) was dissolved in 5 mL of dichloromethane, followed by the addition of triethylamine (47 mg, 0.46 mmol), and then acetyl chloride (35 mg, 0.44 mmol). The system was stirred at room temperature for 12 h, and TLC monitoring showed that there was no residual raw material. 10 mL of water was added to the reaction solution, and dichloromethane was extracted (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The product was separated and purified by column chromatography (dichloromethane: methanol = 40: 1-20: 1) to obtain the final product 13' (10 mg, yield 17%) MS m / z (ESI): 494.2 [M+1]

[0756] 1 H NMR (600MHz, CD3OD) δ8.11(d,J=8.2Hz,1H),7.27(s,1H),7.24-7.10(m,4H),4.06(t,J=6.4Hz,2H),3.78(t,J=6. 8Hz,2H),3.60(s,3H),2.76(s,3H),2.75-2.68(m,2H),2.62(t,J=6.8Hz,2H),2.35(s,6H),1.97(d,J=6.4Hz,6H).

[0757] Embodiment 67:

[0758]

[0759] Synthesis of the final product (Compound 14'):

[0760] Compound 8' (100 mg, 0.22 mmol) was dissolved in 5 mL of dichloromethane solution, followed by the addition of 3-thiopheneboric acid (57 mg, 0.44 mmol), triethylamine (112 mg, 1.1 mmol), 4A MS (150 mg) and copper acetate (80 mg, 0.44 mmol), and replaced with oxygen three times to place the entire system under an oxygen atmosphere. The system was reacted at room temperature for 10 h, and TLC monitoring and tracking was performed until no raw material remained. The solvent was removed under reduced pressure, and the product was separated and purified by column chromatography (dichloromethane: methanol = 30:1-20:1) to obtain the final product 14' (85 mg, yield 71%). MS m / z (ESI): 536.2 [M+1]

[0761] 1 H NMR (600MHz, CD3OD) δ7.71(dd,J=3.2,1.2Hz,1H),7.66(dd,J=5.2,3.2Hz,1H),7.43(dd,J=5.2,1.4Hz,1H),7.34(s,1H),7.22-7.11(m,5H), 4.12(t,J=6.8Hz,2H),3.73(t,J=6.8Hz,2H),3.51(s,3H),2.75(t,J=6.8Hz,2H),2.61(t,J=7.0Hz,2H),2.33(s,6H),1.94(d,J=8.0Hz,6H).

[0762] Embodiment 68:

[0763]

[0764] Synthesis of intermediate 15a':

[0765] Intermediate 7a' (5.90 g, 25.5 mmol) was dissolved in 100 mL of tetrahydrofuran, followed by the addition of N, N-diisopropylethylamine (9.90 g, 76.6 mmol), 4-dimethylaminopyridine (624 mg, 5.1 mmol) and di-tert-butyl dicarbonate (11.15 g, 51.1 mmol). After reacting at 15 °C for 3 h, the temperature was raised to 60 °C for 10 h. TLC monitored the reaction to be complete. N, N'-dimethylethylenediamine (15.0 g) was added to the reaction solution and stirred for 0.5 h. 50 mL of saturated citric acid aqueous solution was added and stirred for 0.5 h. The aqueous phase was extracted with ethyl acetate (30 mL × 2), the organic phase was collected, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 15a' (8.70 g, crude product). It was used directly in the next step without purification. MSm / z(ESI):331.0[M+1]

[0766] Synthesis of intermediate 15b':

[0767] Intermediate 15a' (6.70 g, 20.2 mmol) was dissolved in 100 mL of ethanol and 40 mL of water, followed by iron powder (5.65 g, 101.2 mmol) and ammonium chloride (10.8 g, 202.3 mmol). The system was evacuated and replaced with nitrogen three times, and reacted at 80 ° C for 10 h. TLC monitored the reaction to be complete. The organic phase was filtered and concentrated, and then 50 mL of water was added, extracted with ethyl acetate (50 mL x 2), the organic phase was collected, washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 15b' (3.20 g, yield 53%). No purification was required and it was directly used in the next step. MS m / z (ESI): 301.0 [M+1]

[0768] Synthesis of intermediate 15c':

[0769] The intermediate 15b' (2.00 g, 6.6 mmol) was dissolved in 20 mL of 1,2-dichloroethane, and then chloroacetaldehyde (3.91 g, 19.9 mmol) was added. The system was reacted at 10 ° C for 0.5 h. Sodium triacetoxyborohydride (9.85 g, 46.5 mmol) was added and reacted at 10 ° C for 10 h. TLC monitored the reaction to be complete. 50 mL of water was added to quench the reaction, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The dichloromethane was extracted (50 mL × 2), the organic phase was collected, washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain intermediate 15c' (1.00 g, yield 41%). MS m / z (ESI): 365.0 [M+1]

[0770] Synthesis of intermediate 15d':

[0771] The intermediate 15c' (1.00 g, 2.7 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by the addition of potassium carbonate (1.52 g, 11.0 mmol), sodium iodide (206 mg, 1.4 mmol) and dimethylamine hydrochloride (673 mg, 8.3 mmol). The system was reacted at 80 °C for 10 h. TLC monitored the reaction to be complete. 50 mL of water was added to the system, and dichloromethane was extracted (30 mL × 2). The organic phase was collected, washed with saturated sodium chloride aqueous solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate: methanol: methylamine = 1:1:0:0.01-0:3:1:0.01) to obtain the intermediate 15d' (0.50 g, yield 49%). MS m / z (ESI): 372.1 [M+1]

[0772] Synthesis of intermediate 15e':

[0773] Intermediate 15d' (0.50 g, 1.4 mmol) was dissolved in 2 mL of ethyl acetate, and then 4 M hydrochloric acid ethyl acetate solution (20 mL) was added. The system was reacted at room temperature for 2 h. The reaction was complete by liquid chromatography-mass spectrometry. The organic solvent was concentrated, the residue was dissolved in 15 mL of acetonitrile, potassium carbonate (0.30 g) was added, and the organic phase was filtered and concentrated to obtain intermediate 15e' (0.40 g, crude product). It was used directly in the next step without purification. MS m / z (ESI): 272.0 [M+1]

[0774] Synthesis of intermediate 15f':

[0775] The intermediate 15e' (0.20 g, 0.73 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and then N,N'-thiocarbonyldiimidazole (1.31 g, 7.4 mmol) was added. The system was reacted at 80°C for 15 h. TLC monitored the reaction to be complete. 20 mL of water was added to the system, and dichloromethane was extracted (20 mL×2). The organic phase was collected, washed with saturated sodium chloride aqueous solution (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 30:1-0:1) to obtain the intermediate 15f' (0.25 g, yield 72%). MS m / z (ESI): 316.0 [M+1]

[0776] Synthesis of the final product (Compound 15'):

[0777] Intermediate 15f' (0.20 g, 0.64 mmol) and intermediate 8b' (476 mg, 1.3 mmol) were dissolved in dioxane (3 mL) and water (0.3 mL), followed by the addition of potassium carbonate (176 mg, 1.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (47 mg, 0.064 mmol), and the mixture was evacuated and replaced with nitrogen three times. The system was reacted at 100 °C for 4 h. The reaction was complete by liquid chromatography-mass spectrometry. The organic phase was filtered and concentrated, and purified by column chromatography (dichloromethane: methanol = 30:1-20:1) to obtain the final product 15' (44 mg, yield 14%). MS m / z (ESI): 482.2 [M+1]

[0778] 1H NMR (600 MHz, DMSO-d6) δ 7.55 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.32-7.17 (m, 3H), 4.38 (t, J = 6.8 Hz, 2H), 3.75 (s, 3H), 3.66 (t, J = 7.4 Hz, 2H), 3.49 (s, 3H), 3.32 (s, 2H), 2.61 (t, J = 6.8 Hz, 2H), 2.20 (s, 6H), 1.85 (s, 3H), 1.79 (s, 3H). Example 69:

[0779]

[0780] Synthesis of intermediate 16a':

[0781] 6-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (0.25 g, 1.1 mmol) was dissolved in 3 mL of N,N-dimethylformamide, and sodium hydride (0.17 g, 4.4 mmol, 60%) was added at 0°C. After the system was stirred for 10 minutes, N,N-dimethyl-2-chloroethylamine hydrochloride (0.31 g, 2.2 mmol) was added, and the system was reacted at room temperature for 10 hours. TLC monitoring showed that the reaction was complete. The solution was quenched with aqueous ammonium chloride (2 mL), concentrated, and then water (20 mL) and dichloromethane (20 mL) were added and separated. The aqueous phase was extracted with dichloromethane (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated to obtain intermediate 16a' (0.30 g, yield 73%). It was used directly in the next step without purification. MS m / z(ESI):298.2[M+1]

[0782] Synthesis of the final product (Compound 16'):

[0783] Intermediate 16a' (0.15g, 0.5mmol) and intermediate 8b' (376mg, 1.01mmol) were dissolved in dioxane (5mL) and water (1mL), and potassium carbonate (208mg, 1.5mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (29mg, 0.04mmol) were added. The system was reacted at 100°C for 12h under nitrogen. Liquid chromatography showed that the reaction was complete. After cooling, the mixture was filtered and the filtrate was concentrated. The final product 16' (63mg, yield 24%) was obtained by column chromatography separation and purification (dichloromethane: methanol = 30:1-20:1). MS m / z (ESI): 466.3 [M+1]

[0784] 1H NMR(600MHz,CD3OD)δ7.37-7.30(m,1H),7.29-7.25(m,2H),7.17-7.13(m,3H),4.43(t,J=5.6Hz,2H),3 .92-3.88(m,5H),3.63(t,J=5.6Hz,2H),3.47(s,3H),3.06(s,6H),2.76(t,J=6.0Hz,2H),2.25(s,6H).

[0785] Embodiment 70:

[0786]

[0787] Synthesis of intermediate 17a':

[0788] Potassium fluoride (438 mg, 7.6 mmol) was dissolved in 5 mL of water, followed by the addition of aluminum chloride (865 mg, 8.5 mmol). The system was reacted at 10 °C for 1 h, and water was removed under reduced pressure to obtain a crude product. The crude product and 6-bromo-2,3-dihydro-1H-indole (0.40 g, 1.9 mmol) were dissolved in 15 mL of acetonitrile, and 2-chloroethyldimethylamine hydrochloride (326 mg, 2.2 mmol) was added, and the reaction was carried out at 80 °C for 3 h. TLC monitoring and tracking was performed until no raw material remained. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated sodium chloride (30 mL × 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was separated and purified by column chromatography (dichloromethane: methanol = 40:1) to obtain intermediate 17a' (250 mg, yield 47%). MS m / z (ESI): 283.0 [M+1]

[0789] Synthesis of the final product (Compound 17'):

[0790] The intermediate 17a' (150 mg, 0.53 mmol) was dissolved in 5 mL of tetrahydrofuran and 0.5 mL of water, and then the intermediate 8b' (396 mg, 1.1 mmol), potassium carbonate (146 mg, 1.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (39 mg, 0.53 mmol) were added, and the atmosphere was replaced with nitrogen three times. The whole system was placed under a nitrogen atmosphere, and the reaction was stirred at 100 ° C for 10 hours, and TLC monitoring and tracking was performed until there was no raw material left. The solvent was removed under reduced pressure, and the product was directly separated and purified by column chromatography (dichloromethane: methanol = 20:1) to obtain the final product 17' (26 mg, yield 10%). MS m / z (ESI): 482.2 [M+1]

[0791] 1H NMR (600MHz, DMSO-d6) δ7.32-7.24(m,2H),7.19(br d,J=3.2Hz,2H),7.13-7.05(m,2H),3.76(br t,J=6.6Hz,2H),3.66(br t,J=7.4Hz,2H),3.60(s,2H),3.52(s,3H),2.47-2.43(m,4H),2.16(s,6H),1.91(s,3H),1.84(s,3H).

[0792] Experimental Example 1: Cell-level screening activity data of NMT inhibitors

[0793] Purpose of screening:

[0794] The cytopathic effect (CPE) assay was used to detect the in vitro anti-human rhinovirus (HRV) activity of the compounds.

[0795] Screening system:

[0796] HeLa cells infected with HRV.

[0797] HRV subtypes: HRV 1b; HRV 14.

[0798] Test method:

[0799] Compounds (3-fold serial dilutions, 8 concentration points, duplicate wells) and viruses were added to 384-well cell culture plates and incubated at 5% CO2, 33°C for 1 hour. H1 HeLa cells were then seeded into the test plate at a density of 15,000 cells per well and cultured in a 5% CO2, 33°C incubator for 2 days until the cytopathic effect in the virus-infected control wells without the compound reached 80-95%. The final concentration of DMSO was 0.5%. The antiviral activity of the compound is represented by the inhibition rate (%) of the virus-induced cytopathic effect of the compound at different concentrations. The calculation formula is as follows:

[0800] Inhibition rate (%) = (test well reading - virus control average) / (cell control average - virus control average) × 100

[0801] GraphPad Prism software was used to perform nonlinear fitting analysis on the inhibition rate of the compounds and calculate the half effective concentration (EC 50 )value.

[0802] Compound screening results:

[0803] Table 1 Data on the inhibitory activity of compounds against rhinovirus

[0804]

[0805]

[0806]

[0807] Test conclusion: According to the data in the table, the compounds of the present invention have a strong inhibitory effect on human rhinovirus (HRV 1B and HRV 14 subtypes).

[0808] Experimental Example 2: In vitro inhibitory effect of NMT inhibitor on SU-DHL-2 / MIA PaCa-2 cell proliferation

[0809] 1. Purpose of the experiment

[0810] To investigate the inhibitory effects of synthetic compounds on cell proliferation in vitro.

[0811] 2. Test Principle

[0812] MTT, also known as Thiazolyl Blue, is a tetrazolium salt of a dye that can accept hydrogen atoms. The amber dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to insoluble blue-purple crystals and deposit them in the cells, while dead cells do not have this function. Dimethyl sulfoxide can dissolve the blue-purple complex in the cells, and its light absorption value is measured at a wavelength of 490-550nm using an enzyme-linked immunosorbent assay, which can indirectly reflect the number of cells. Within a certain range of cell numbers, the amount of MTT crystals formed is proportional to the number of cells. The drug to be tested is diluted into different concentrations in turn and added to a 96-well plate. After the drug has acted for a certain period of time, its OD value is measured. The size of the OD value can reflect the number of living cells, and its IC is calculated using SPSS19.0. 50 value.

[0813] 3. Test equipment

[0814] Model 371 CO2 Incubator: Thermo

[0815] IX70-142 inverted fluorescence microscope: Olympus

[0816] HFsafe-1500 Biological Safety Cabinet: Shanghai Lishen Scientific Instrument Co., Ltd.

[0817] Varloskan flash microplate reader: Thermo

[0818] Precision electronic balance: Mettler AL204

[0819] 4. Test materials:

[0820] 4.1 Cells and culture medium

[0821]

[0822] 4.2 Test materials

[0823] name Specification Manufacturer Fetal bovine serum 500mL / bottle Cellmo PBS 500mL / bottle Solarbio DMSO 500mL / bottle recovery MTT 5g / bottle Amresco

[0824] 4.3 Reagent preparation

[0825] 5 mg / mL MTT working solution: Weigh 0.5 g of MTT and dissolve it in 100 mL of PBS, filter it through a 0.22 μm microporous filter to sterilize it, and place it in a 4°C refrigerator (for use within two weeks) or -20°C for long-term storage.

[0826] 5. Test methods

[0827] 5.1 Paving

[0828] Suspended cells: Count after centrifugation and resuspending. Prepare a cell suspension of a certain density with complete culture medium, pipette and evenly inoculate in a 96-well plate, 100 μL per well, and then culture in a CO2 incubator.

[0829] 5.2 Drug preparation

[0830] Weigh an appropriate amount of drug and add calculated amount of DMSO to dissolve, package, and store at -20℃; prepare a concentration of 10mM

[0831] 5.3 Dosing

[0832] The drugs were diluted to several concentrations and added to the 96-well plate inoculated with cells, and cultured in a CO2 incubator.

[0833] 6. Detection

[0834] The 96-well plate was taken out and the cell confluence was observed under a microscope. The MTT method was used for detection.

[0835] MTT method: add 20 μL of MTT to each well, incubate in an incubator for about 4 hours, discard the liquid in the wells, add 150 μL of DMSO to each well, place on an oscillator for 5-10 minutes, and detect with an enzyme-labeled instrument at a wavelength of 550 nm.

[0836] 7. Data analysis was performed using SPSS 19.0 statistical software to calculate the IC of the drug 50 value.

[0837] The compound screening results are shown in Table 2:

[0838] Table 2 Cell proliferation inhibition test data of compounds

[0839]

[0840]

[0841] Experimental conclusion: According to the data in the table, the compounds of the present invention have a strong inhibitory effect on SU-DHL-2 and MIA CaPa-2 cells.

[0842] Experimental Example 3: Experiment on the proliferation inhibition of other tumor cells by NMT inhibitors

[0843] The cells and culture medium used in this test example are as follows:

[0844]

[0845]

[0846] The test method of this test is the same as that of Test Example 2, and the test results are as follows:

[0847] Table 3 The data of inhibition of proliferation of various tumor cells by some compounds

[0848]

[0849] Experimental conclusion: According to the data in the table, the compounds of the present invention have a strong in vitro proliferation inhibitory effect on a variety of human tumor cells.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, X is selected from -(CH2) r -, wherein r is selected from 2; Y does not exist; R 1 independently selected from -F, -Cl, -Br; n is 0, 1, 2 or 3; A is pyrazolyl or imidazolyl; R 4 Independently selected from unsubstituted C 1-6 alkyl; p is 1, 2 or 3; W is selected from C, N or O; when W is O, R 3 for not existing; R 2 Selected from unsubstituted C 1-6 Alkyl, -(CH2) w NR 11 R 12 ; R 3 Selected from -H, unsubstituted or t R 13 Substituted C 1-6 Alkyl, thienyl, unsubstituted C 1-6 Alkoxy, -(CH2) w NR 11 R 12 、-(CH2) w C(O)R 11 ; w＝0，1，2； t＝1； R 11 and R 12 are each independently selected from -H, unsubstituted C 1-6 alkyl; R 13 Selected from -F, -Cl, -Br, -OH, -CN, -NO2, -N3, SH, NH2, -C≡CH or C 1-6 Alkoxy; Z is selected from O or S.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that It has the structure shown in formula (II): in, R 1 for -F; R 16 Independently selected from C 1-6 alkyl; R 17 Same definition as R 4 ; u is 1 or 2.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that R 16 are independently selected from methyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that It has the structure shown in formula (III):

5. A compound or a pharmaceutically acceptable salt thereof, characterized in that Has the following structure:

6. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

7. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof for preparing an N-myristoyltransferase inhibitor for treating or preventing human rhinovirus infection.

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