CN116102541A - Compounds as NMT inhibitors and uses thereof - Google Patents
Compounds as NMT inhibitors and uses thereof Download PDFInfo
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- CN116102541A CN116102541A CN202310199913.XA CN202310199913A CN116102541A CN 116102541 A CN116102541 A CN 116102541A CN 202310199913 A CN202310199913 A CN 202310199913A CN 116102541 A CN116102541 A CN 116102541A
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Abstract
The present invention provides compounds having N-myristoyl transferase (NMT) inhibitor activity or pharmaceutically acceptable salts thereof and methods for preparing the same. The invention also relates to the use of such compounds as inhibitors of N-myristoyltransferase (NMT) for the preparation of a medicament for the treatment or prophylaxis of infectious diseases, including protozoal infections, such as malaria and leishmaniasis, and viral infections, such as human rhinovirus and HIV, or hyperproliferative diseases, including lymphomas, leukemias, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer, colorectal cancer, etc.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a compound serving as an NMT inhibitor and application of the compound or a pharmaceutical composition in preparation of medicines.
Background
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 (NMT 1 and NMT 2), both expressed in most tissues. Typical substrates for NMT include tyrosine kinases pp60c-src and pp60c-yes, BID, and their potential substrates are wide, and it is currently found that more than 100 myristoylable proteins are distributed at different positions of cells and have different biological functions, mainly involved in important biological processes such as secondary signal transduction, vesicle transport, viral maturation and tumor formation (overexpression in tumor cells). NMT may be involved in the development and progression of many diseases, such as cancer, epilepsy, alzheimer's disease, noonan-like syndrome, viral and bacterial infections, and the like.
Rhinovirus (RV) is the primary causative agent of the common cold, and is also responsible for asthma, chronic obstructive pulmonary disease, cystic fibrosis, etc., but no targeted treatment is currently available. Ed Tate et al found that rhinoviruses, upon infecting the host, the host's ribosomal genome translated into a multimeric protein, and that the host's N-myristoyltransferase NMT produced a myristoylation modification at the N-terminus of the protein to form a capsid protein precursor. Subsequently, the proteases of the rhinoviruses cleave the polyprotein into three parts VP0, VP3 and VP1, which are assembled into protomers (protomers), 5 protomers are assembled into pentameric complexes (pentamers), and finally 12 pentamers are assembled together with the RNA genome into viruses with infectious capacity. Previous mutation experiments demonstrated that myristoylation modification on VP0 is critical for viral capsid protein assembly, so inhibition of NMT prevents rhinovirus infection and self replication. Because of the commonality of this viral mechanism, it can inhibit a variety of members of the picornafamily of viruses including rhinoviruses, polioviruses, foot and mouth disease viruses, hepatitis a viruses.
According to published data, IMP INNOVATIONS LTD has been filed for related invention patent (WO 2017001812) directed to NMT inhibitors, primarily for rhinovirus and HIV infection, malaria, and other diseases. In addition, companies STEPHEN, ADIR, SEARLE & CO, etc. have also obtained relevant patent approval for NMT inhibitors and their use (WO 2010026365; US5266576; US 5942600). In recent years, companies such as VASTCON INC and SHRIVASTAV ANURAAG have filed a patent related to the use of NMT in tumors (WO 2017190241; WO 2014082178). Based on these studies and findings, it was shown that inhibition of NMT may provide benefits in the treatment of a variety of picornaviridae and tumors.
Although some small molecules of NMT inhibitors have been disclosed at present, there is still a need to develop new compounds with better drug effect and drug generation result, and through continuous exploration, the present invention designs compounds with structures shown in general formula (I), and finds that the compounds with such structures show excellent effects and actions.
Disclosure of Invention
The object of the present invention is to provide a compound as an N-myristoyltransferase inhibitor or a pharmaceutically acceptable salt thereof, which is useful for the manufacture of a medicament for the treatment or prophylaxis of infectious diseases or hyperproliferative diseases, including protozoal infections, such as malaria and leishmaniasis, viral infections, such as human rhinoviruses and HIV, hyperproliferative disorders, such as lymphomas (in particular such as B-cell lymphomas), leukemias, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer and colorectal cancer.
Specifically disclosed is a compound represented by the formula (I) below or a pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
w is selected from-O-or-NH-;
Y 1 selected from- (CH) 2 ) r -wherein r is selected from 1,2,3,4 or 5;
Y 2 absence or as
Wherein q is selected from 1,2,3 or 4;
R 1 independently selected from-F, -Cl, -Br, -CN, -OR 5 、-NR 5 R 6 、-NO 2 、-N 3 、C 1-6 Alkyl, -COOR 5 or-CONR 5 R 6 ，R 5 And R is 6 Each independently selected from H, C 1-6 An alkyl group;
n is 0,1,2 or 3;
a is heteroaryl;
R 4 independently selected from the group consisting of-F, -Cl-Br, -OH, -CN, -NO 2 、-N 3 、-SR 7 、-(CH 2 ) m C(O)R 7 、-(CH 2 ) m NR 7 R 8 、-(CH 2 ) m S(O)R 7 、-(CH 2 ) m S(O) 2 R 7 、-(CH 2 ) m OC(O)R 7 、-(CH 2 ) m C(O)OR 7 、-(CH 2 ) m OS(O) 2 R 7 、-(CH 2 ) m S(O) 2 OR 7 、-(CH 2 ) m C(O)NR 7 R 8 、-(CH 2 ) m S(O) 2 NR 7 R 8 、-(CH 2 ) m NR 7 C(O)R 8 、-(CH 2 ) m NR 7 S(O) 2 R 8 、-(CH 2 ) m NHC(＝NH)NR 7 R 8 、-(CH 2 ) 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 group,
m＝0，1，2，3，4；
s=0, 1,2,3,4,5 or 6;
R 7 and R is 8 Each independently selected from-H, -NH 2 -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 carbocyclyl, unsubstituted or s R 10 Substituted heterocyclyl;
or R is 7 And R is 8 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 9 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、-SH、-NH 2 (C.ident.CH, -COOH or C) 1-6 An alkoxy group;
each R 10 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、-SH、-NH 2 (C.ident.CH), unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 An alkoxy group;
p is 0,1,2,3 or 4;
Z 1 、Z 2 c or N, and C is H or R 1 Substitution;
Z 3 、Z 4 is CH orN；
Z 6 Is C or N;
Z 5 selected from S or O;
L＝-(CH 2 ) w -, wherein one or more H may be substituted with D;
w＝0，1，2，3，4；
R 2 selected from-C (O) R 11 、-NR 11 R 12 、-S(O)R 11 、-S(O) 2 R 11 、-OC(O)R 11 、-C(O)OR 11 、-OS(O) 2 R 11 、-S(O) 2 OR 11 、-NR 11 C(O)R 12 、-NR 11 S(O) 2 R 12 、-C(O)NR 11 R 12 、-S(O) 2 NR 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 ；
t=0, 1,2,3,4,5 or 6;
R 11 and R is 12 Each independently selected from-H, -NH 2 -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 carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
or R is 11 And R is 12 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 13 Each independently selected from the group consisting of-D, -F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
R 14 selected from unsubstituted or t R 15 Substituted aryl, unsubstituted or t R 15 Substituted heteroaryl, unsubstituted or t R 15 Substituted carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
each R 15 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、-SH、-NH 2 (C.ident.CH), unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 An alkoxy group;
when Z is 6 When N is present, R 3 Absence of; when Z is 6 When C is R 3 Selected from-H, -CH 3 、CHX 2 、CH 2 X、-CX 3 、-(CH 2 ) v OH、-(CH 2 ) v CN、-(CH 2 ) v C≡CH、-OR 16 、-(CH 2 ) v COOH、-(CH 2 ) v NO 2 、-(CH 2 ) v NR 16 R 17 or-CONR 16 R 17 ，R 16 And R is 17 Each independently selected from H or C 1-6 Alkyl, X is halogen;
v＝0，1，2，3，4；
unless otherwise indicated, aryl groups as described above contain 6 to 14 carbon atoms; carbocyclyl groups contain 3 to 10 carbon atoms and are non-aromatic; heteroaryl is a 5-to 10-membered heteroaryl; and the heterocyclic group is 3-10 membered heterocyclic group and is of a non-aromatic structure; heteroaryl or heterocyclyl contains one, two or more heteroatoms selected from N, O or S, the remainder being carbon atoms.
Further, the invention is described above as C 1-6 Alkyl means a saturated alkane containing 1, 2, 3, 4, 5 or 6 carbon atoms in the alkyl chain, which may be of straight or branched structure, and specifically may be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl. The invention is as described above C 1-6 C in alkoxy 1-6 Alkyl moieties are also defined and selected as such.
The aryl group of the present invention as described above 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, anthryl, phenanthryl, pyrenyl, and the like.
The heteroaryl group of the present invention is a 5-to 10-membered structure, preferably a 5-to 8-membered structure, more preferably a 5-to 6-membered structure, as described above, 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, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, or benzophthalazinyl, etc.
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein a is a 5-to 6-membered heteroaryl containing 2-3 heteroatoms selected from N or O; r is R 1 Independently selected from-F, -Cl or-CH 3 。
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein a is selected from pyrazolyl or imidazolyl; y is Y 1 is-CH 2 -，Y 2 Is that
Wherein q is selected from 1 or 2.
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein a is selected from pyrazolyl or imidazolyl; y is Y 1 Is- (CH) 2 ) 2 -，Y 2 Is absent.
Further, in certain embodiments, the compounds of the present invention as described above, or pharmaceutically acceptable salts thereof, have the structure of formula (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 18 independently selected from C 1-6 Alkyl, preferably methyl;
R 19 r in the same formula (I) 4 ；
u is 1 or 2;
the remaining variables are as defined for formula (I).
Further, in certain embodiments, the compounds of the present invention as described above, or pharmaceutically acceptable salts thereof, have the structure of formula (III):
wherein R is 19 R in the same formula (I) 4 ；
The remaining variables are as defined for formula (I).
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein, when Z 6 When N is present, R 3 Absence of; when Z is 6 When C is R 3 Selected from the group consisting of-H, methyl, ethyl, propyl, isopropyl, -CX 3 、-(CH 2 ) v OH、-OR 16 、-CH 2 NR 16 R 17 or-CONR 16 R 17 。
Further preferred, in certain embodiments, are compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein Z 6 Is C, R 3 H.
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein Z 5 S.
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein R 2 Selected from-NR 11 R 12 ；
R 11 And R is 12 Each independently selected from unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 An alkoxy group;
or R is 11 And R is 12 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S.
Advancing oneFurther, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein R 4 Independently selected from the group consisting of-F, -Cl-Br, -OH, -CN, -NO 2 、-N 3 、-SR 7 、-C(O)R 7 、-C(O)OR 7 、-C(O)NR 7 R 8 、-NR 7 S(O) 2 R 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 An alkoxy group;
s=0, 1,2,3,4,5 or 6;
R 7 and R is 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 carbocyclyl, unsubstituted or s R 10 Substituted heterocyclyl;
or R is 7 And R is 8 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 9 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、-SH、-NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
each R 10 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、-SH、-NH 2 (C.ident.CH), unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 An alkoxy group.
Further, in certain embodiments, the compounds of the invention as described above, or pharmaceutically acceptable salts thereof, wherein W is-O-.
The invention also provides a compound shown in the formula (IV) or pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from- (CH) 2 ) r -wherein r is selected from 1,2,3,4 or 5;
y is absent or is
Wherein q is selected from 1,2,3 or 4;
R 1 independently selected from-F, -Cl, -Br, -CN, -OR 5 、-NR 5 R 6 、-NO 2 、-N 3 、-COOR 5 or-CONR 5 R 6 ，R 5 And R is 6 Each independently selected from H, C 1-6 An alkyl group;
n is 0,1,2 or 3;
a is heteroaryl;
R 4 Independently selected from the group consisting of-F, -Cl-Br, -OH, -CN, -NO 2 、-N 3 、-SR 7 、-(CH 2 ) m C(O)R 7 、-(CH 2 ) m NR 7 R 8 、-(CH 2 ) m S(O)R 7 、-(CH 2 ) m S(O) 2 R 7 、-(CH 2 ) m OC(O)R 7 、-(CH 2 ) m C(O)OR 7 、-(CH 2 ) m OS(O) 2 R 7 、-(CH 2 ) m S(O) 2 OR 7 、-(CH 2 ) m C(O)NR 7 R 8 、-(CH 2 ) m S(O) 2 NR 7 R 8 、-(CH 2 ) m NR 7 C(O)R 8 、-(CH 2 ) m NR 7 S(O) 2 R 8 、-(CH 2 ) m NHC(＝NH)NR 7 R 8 、-(CH 2 ) 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 An alkoxy group;
m＝0，1，2，3，4；
s=0, 1,2,3,4,5 or 6;
R 7 and R is 8 Each independently selected from-H, -NH 2 -OH, 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 carbocyclyl, unsubstituted or s R 10 Substituted heterocyclyl;
or R is 7 And R is 8 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 9 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
each R 10 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH), unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 An alkoxy group;
p is 0,1,2,3 or 4;
w is selected from C, N or O; when W is O, R 3 Is absent;
R 2 and R is 3 Are each independently selected from-H, - (CH) 2 ) w C(O)R 11 、-(CH 2 ) w NR 11 R 12 、-(CH 2 ) w S(O)R 11 、-(CH 2 ) w S(O) 2 R 11 、-(CH 2 ) w OC(O)R 11 、-(CH 2 ) w C(O)OR 11 、-(CH 2 ) w OS(O) 2 R 11 、-(CH 2 ) w S(O) 2 OR 11 、-(CH 2 ) w NR 11 C(O)R 12 、-(CH 2 ) w NR 11 S(O) 2 R 12 、-(CH 2 ) w C(O)NR 11 R 12 、-(CH 2 ) w S(O) 2 NR 11 R 12 Unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, - (CH) 2 ) w R 14 ；
w＝0，1，2，3，4；
t=0, 1,2,3,4,5 or 6;
R 11 And R is 12 Each independently selected from-H, -NH 2 -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 carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
or R is 11 And R is 12 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 13 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
R 14 selected from unsubstituted or t R 15 Substituted aryl, unsubstituted or t R 15 Substituted heteroaryl, unsubstituted or t R 15 Substituted carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
each R 15 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH), unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 An alkoxy group;
z is selected from O or S;
unless otherwise indicated, the aryl groups described in formula (IV) above contain 6 to 14 carbon atoms; carbocyclyl groups contain 3 to 10 carbon atoms and are non-aromatic; heteroaryl is a 5-10 membered heteroaryl; and the heterocyclic group is a 3-10 membered heterocyclic group and is a non-aromatic structure; heteroaryl or heterocyclyl contains one, two or more heteroatoms selected from N, O or S, the remainder being carbon atoms.
Further, the C in the formula (IV) of the present invention 1-6 Alkyl means a saturated alkane containing 1, 2, 3, 4, 5 or 6 carbon atoms in the alkyl chain, which may be of straight or branched structure, and specifically may be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, straight or branched pentyl, straight or branched hexyl. The invention is characterized in that C in the formula (IV) 1-6 C in alkoxy 1-6 Alkyl moieties are also defined and selected as such.
The aryl group of 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, anthryl, phenanthryl, pyrenyl, and the like.
The heteroaryl group in the formula (IV) of the present invention has a 5-10-membered structure, preferably a 5-8-membered structure, more preferably a 5-6-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, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, or benzophthalazinyl, etc.
Further, in certain embodiments, the compounds of formula (IV) of the present invention or pharmaceutically acceptable salts thereof, wherein a is a 5-to 6-membered heteroaryl group containing 2 to 3 heteroatoms selected from N or O; r is R 1 Independently selected from-F or-Cl.
Further, in certain embodiments, the compounds of formula (IV) of the present invention or pharmaceutically acceptable salts thereof, wherein a is selected from pyrazolyl or imidazolyl.
Further, in certain embodiments, the compounds of formula (IV) of the present invention, or pharmaceutically acceptable salts thereof, have the structure of formula (v):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is-F;
R 16 independently selected from C 1-6 Alkyl, preferably methyl;
u is 1 or 2;
R 17 definition is as same as R 4 ；
R 1 、R 2 、R 3 W, Z and n are as shown in the aforementioned formula (IV).
Further, in certain embodiments, the compounds of formula (IV) of the present invention, or pharmaceutically acceptable salts thereof, have the structure of formula (vi):
wherein R is 1 、R 2 、R 3 W, Z and n are as shown in the formula (IV), R 17 The definition is shown in the formula (V).
Further, in certain embodiments, the compounds of formula (IV), formula (V) or formula (vi) of the invention, or pharmaceutically acceptable salts thereof, wherein W is selected from N.
In certain embodiments, the compounds of formula (IV), formula (V) or formula (vi) of the invention, or pharmaceutically acceptable salts thereof, wherein W is selected from O.
In certain embodiments, the compounds of formula (IV), formula (V) or formula (vi) of the invention, or pharmaceutically acceptable salts thereof, wherein W is selected from C.
Further, in certain embodiments, a compound of formula (IV), formula (V) or formula (VI) of the invention, or a pharmaceutically acceptable salt thereof, wherein R 2 Is- (CH) 2 ) w NR 11 R 12 。
Preferably, R 2 Is- (CH) 2 ) 2 N(CH 3 ) 2 。
Further, in certain embodiments, a compound of formula (IV), formula (V) or formula (VI) of the 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 aforementioned formula (IV).
Further, in certain embodiments, a compound of formula (IV), formula (V) or formula (VI) of the invention, or a pharmaceutically acceptable salt thereof, wherein R 3 is-H or C 1-6 An alkyl group.
The compound of the present invention or a pharmaceutically acceptable salt thereof has the following structure:
the invention also provides a pharmaceutical composition.
The invention provides a medicinal composition which comprises the compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
It is a further object of the present invention to provide the use of said compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
First, the present invention provides the use of said compound or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the manufacture of a medicament as an N-myristoyltransferase inhibitor.
The invention also provides application of the compound or pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating or preventing infectious diseases.
Further, in the above-mentioned uses, the infectious disease includes a protozoan infectious disease or a viral infectious disease.
Further, in the above-mentioned uses, the protozoan infection diseases are malaria and leishmaniasis.
Further, in the above-mentioned uses, the virus-infected disease is human rhinovirus-infected disease and HIV-infected disease.
In addition, the invention also provides the application of the compound or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing medicines for treating or preventing hyperproliferative diseases.
Further, in the above-mentioned uses, the hyperproliferative disease is lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, stomach cancer, liver cancer, colorectal cancer.
Still further in the above use, the hyperproliferative disease is B cell lymphoma.
The present invention provides a process for preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, which process comprises:
synthesis scheme 1:
the compounds of formula (IV) of the present invention can be obtained by the synthetic method of synthetic scheme 1: heating the compound (a) and the compound (b) to react under the catalysis of a palladium catalyst to generate a compound (c); removing methyl from the compound (c) under the action of Lewis acid (such as boron tribromide) to obtain a compound (d); and heating the compound (d) and the compound (e) under the alkaline condition to obtain a target product (f). Wherein R is 1 、R 2 、R 3 、R 4 X, A, W, Y, Z, n and p have the meaning as described for formula (IV) of the invention; LG is a leaving group selected from chloro, bromo, iodo, methanesulfonyl or p-toluenesulfonyl.
Synthesis scheme 2:
the compounds of formula (IV) of the present invention can be obtained by the synthetic method of synthetic scheme 2: heating the compound (g) and the compound (b) to react under the catalysis of a palladium catalyst to generate a compound (d); and heating the compound (d) and the compound (e) under the alkaline condition to obtain a target product (f). R is R 1 、R 2 、R 3 、R 4 X, A, W, Y, Z, n and p have the meaning as described for formula (IV) of the invention; LG is a leaving group selected from chloro, bromo, iodo, methanesulfonyl or p-toluenesulfonyl.
Synthesis scheme 3:
the compounds of formula (IV) of the present invention can be obtained by the synthetic method of synthetic scheme 3: the compound (d) and the compound (h) are subjected to a casting reaction to produce the target product (f). Wherein R is 1 、R 2 、R 3 、R 4 X, A, W, Y, Z, n and p have the meaning as described for formula (IV) of the invention.
Synthesis scheme 4:
the compounds of formula (IV) of the present invention can be obtained by the synthetic method of synthetic scheme 4: compound (i) and compound (h) are subjected to a casting reaction to form compound (j); under the action of palladium catalyst, the compound (j) can be subjected to a coupling reaction to generate a compound (k); and (3) reacting the compound (k) with the compound (b) under the action of a palladium catalyst to generate a target product (f). Wherein R is 1 、R 2 、R 3 、R 4 X, A, W, Y, Z, n and p have the meaning as described for formula (IV) of the invention.
The beneficial effects of the invention are as follows:
the invention designs a compound with novel structure, and provides a new direction for the development of medicines for resisting protozoal infection or virus infection, especially human rhinovirus interference, and medicines for resisting lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer and colorectal cancer. In vitro cell antiviral activity researches show that the compounds have strong inhibition effects on two subtype viruses of HRV 1B and HRV 14 and also have strong inhibition effects on various tumor cells. The successful synthesis of the drug compound disclosed by the invention expands the drug selection for treating viral infection diseases. In addition, the invention researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The following examples serve to further illustrate the invention in detail, but do not limit it in any way.
In the examples and in the course of the examples process, the letter "A" refers to intermediate A and the letter "A '" refers to intermediate A', which is not the same concept as A in the compound structures of the claims and the summary of the invention.
Example 1:
synthesis of intermediate 1 a:
5-bromobenzothiophene (1.10 g,5.16 mmol) was dissolved in 50mL of methylene chloride, 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, and TLC monitored the starting material for no residue. To the reaction solution was added water (60 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=30:1 to 10:1) to give intermediate 1a (0.60 g, yield 48%).
Synthesis of intermediate 1 b:
intermediate 1a (0.60 g,2.47 mmol) was dissolved in 40mL dioxane followed by 3-fluoro-2-hydroxyphenylboronic acid (0.58 g,3.71 mmol), tetrakis triphenylphosphine palladium (0.20 g,0.17 mmol) and potassium phosphate trihydrate (0.99 g,3.71 mmol) and stirred at 100deg.C for 4 hours, and TLC monitored the starting material for no residue. After cooling, water (60 mL) was added to the reaction solution, extraction was performed 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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1-1:1) to give intermediate 1b (0.30 g, yield 45%).
Synthesis of intermediate 1 c:
intermediate 1b (0.30 g,1.10 mmol) was dissolved in 40mL of dichloromethane, followed by addition of dimethylamine hydrochloride (178 mg,2.20 mmol) and triethylamine (333 mg,3.30 mmol), stirred at room temperature for 5 hours, followed by addition of sodium borohydride acetate (700 mg,3.30 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was slowly added water (60 mL), 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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 1c (150 mg, yield 45%).
Synthesis of intermediate a:
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), reacted at room temperature for 4 hours, TLC monitored the starting material for no remaining, water (20 mL) was added to the system, dichloromethane extraction (20 mL. Times.3), the organic phases were combined, saturated sodium chloride washing (20 mL. Times.2), anhydrous sodium sulfate drying, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate A (1.07 g, 73%).
Synthesis of end product compound 1:
intermediate 1c (150 mg,0.50 mmol) was dissolved in 30mL of 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℃for 3 hours and no starting material remained as monitored by TLC. After cooling, water (40 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 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 the crude product was purified by column chromatography (dichloromethane: methanol=50:1-10:1) to give compound 1 (105 mg, yield 48%).
1 H NMR(600MHz，CD 3 OD)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).
Example 2:
synthesis of intermediate 2 a:
intermediate 1a (0.55 g,2.27 mmol) was dissolved in 40mL dioxane followed by 3-fluoro-2-hydroxyphenylboronic acid (0.53 g,3.41 mmol), palladium tetraphenylphosphine (200 mg,0.17 mmol) and potassium phosphate trihydrate (0.91 g,3.41 mmol) and stirred at 100deg.C for 2.5 hours, and TLC monitored the starting material for no residue. After cooling, water (60 mL) was added to the reaction solution, extraction was performed 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 the crude product was purified by column chromatography (petroleum ether: ethyl acetate=20:1-1:1) to give intermediate 2a (250 mg, yield 40%).
Synthesis of intermediate 2 b:
intermediate 2a (250 mg,0.92 mmol) was dissolved in 40mL 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, then sodium borohydride acetate (635 mg,2.97 mmol) was added, stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was slowly added water (60 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 2b (150 mg, yield 54%).
Synthesis of final product 2:
intermediate 2b (150 mg,0.50 mmol) was dissolved in 30mL of 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℃for 3 hours and no starting material remained as monitored by TLC. After cooling, water (40 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 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 the crude product was purified by column chromatography (dichloromethane: methanol=50:1-10:1) to give compound 2 (125 mg, yield 57%). MS m/z (ESI): 438.2[ M+1]
1 HNMR(600MHz，CD 3 OD)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).
Example 3:
synthesis of intermediate 3 a:
intermediate 1a (0.60 g,2.47 mmol) was dissolved in 40mL dioxane followed by addition of 2-hydroxyphenylboronic acid (0.58 g,3.71 mmol), palladium tetraphenylphosphine (200 mg,0.17 mmol) and potassium phosphate trihydrate (0.99 g,3.71 mmol), and the reaction was stirred at 100deg.C for 2.5 hours, with no starting material remaining as monitored by TLC. After cooling, water (60 mL) was added to the reaction solution, extraction was performed 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 the crude product was purified by column chromatography (petroleum ether: ethyl acetate=
20:1-1:1) to afford intermediate 3a (300 mg, 48% yield).
Synthesis of intermediate 3 b:
intermediate 3a (300 mg,1.18 mmol) was dissolved in 40mL of dichloromethane, followed by the addition of dimethylamine hydrochloride (191 mg,2.36 mmol) and triethylamine (356 mg,3.54 mmol), stirred at room temperature for 5 hours, then sodium borohydride acetate (706 mg,3.30 mmol) was added, stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was slowly added water (60 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 3b (150 mg, yield 45%).
Synthesis of end product compound 3:
intermediate 3b (150 mg,0.59 mmol) was dissolved in 30mL of N, N-dimethylformamide, followed by addition of intermediate A (218 mg,0.71 mmol) and anhydrous potassium carbonate (244 mg,1.77 mmol) and stirring at 50℃for 3 hours, and TLC monitored no starting material remained. After cooling, water (40 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 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 the crude product was purified by column chromatography (dichloromethane: methanol=50:1 to 10:1) to give compound 3 (75 mg, yield 34%).
1 HNMR(600MHz,CDCl 3 )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).
Example 4:
synthesis of intermediate 4 a:
intermediate 1a (320 mg,1.30 mmol) was dissolved in 7mL dioxane followed by 3-methyl-2-hydroxyphenylboronic acid (300 mg,2.00 mmol), palladium tetraphenylphosphine (115 mg,0.10 mmol) and potassium phosphate trihydrate (692 mg,2.60 mmol). The system was reacted at 100℃for 4 hours under nitrogen protection, and TLC monitored no starting material remained. After cooling, water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20×3 mL), 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 the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give intermediate 4a (311 mg, yield 89%).
Synthesis of intermediate 4 b:
intermediate 4a (311 mg,1.16 mmol) was dissolved in 10mL 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, followed by the addition of sodium borohydride acetate (492 mg,2.32 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was added water (20 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 4b (240 mg, yield 69%).
Synthesis of end product compound 4:
intermediate 4b (200 mg,0.67 mmol) was dissolved in 10mL of 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℃and reacted for 3 hours, and TLC monitored no starting material remained. After cooling, water (40 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 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 the crude product was purified by column chromatography (dichloromethane: methanol=50:1-10:1) to give compound 4 (120 mg, yield 41%). MS m/z (ESI): 434.2[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 5:
synthesis of intermediate 5 a:
intermediate 1a (280 mg,1.16 mmol) was dissolved in 7mL dioxane followed by the addition of 3-chloro-2-hydroxyphenylboronic acid (300 mg,1.74 mmol), palladium tetraphenylphosphine (115 mg,0.10 mmol) and potassium phosphate trihydrate (611 mg,2.32 mmol). The system was reacted at 100℃for 4 hours under nitrogen protection, and TLC monitored no starting material remained. After cooling, water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20×3 mL), 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 the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give intermediate 5a (300 mg, yield 95%).
Synthesis of intermediate 5 b:
intermediate 5a (300 mg,1.00 mmol) was dissolved in 10mL 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, followed by the addition of sodium borohydride acetate (424 mg,2.00 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was added water (20 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 5b (240 mg, yield 75%).
Synthesis of end product compound 5:
intermediate 5b (240 mg,0.78 mmol) was dissolved in 10mL of N, N-dimethylformamide, followed by intermediate A (280 mg,0.90 mmol) and anhydrous potassium carbonate (221 mg,1.60 mmol) and stirred at 50℃for 3 hours, and TLC monitored no starting material remained. After cooling, water (40 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20 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 the crude product was purified by column chromatography (dichloromethane: methanol=50:1 to 10:1) to give compound 5 (200 mg, yield 56%). MS m/z (ESI) 454.1[ M+1];
1 H NMR(600MHz,CDCl 3 ) Delta 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:
synthesis of intermediate 6 a:
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 10mL of tetrahydrofuran, diethyl azodicarboxylate (452 mg,2.59 mmol) was added at room temperature, and stirred at room temperature for 2 hours. To the reaction solution was added water (30 mL), the organic phases were combined by extraction with ethyl acetate (20 ml×3), washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give intermediate 6a (120 mg, yield 28%).
Synthesis of intermediate B:
intermediate 1a (2.66 g,11.0 mmol) was dissolved in dichloromethane (100 mL), followed by dimethylamine hydrochloride (1.78 g,22.0 mmol) and triethylamine (3.33 g,33.0 mmol), stirred at room temperature for 5 hours, followed by sodium borohydride acetate (7.00 g,33.0 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was slowly added water (200 mL), 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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate B1 (1.40 g, yield 50%).
Intermediate B1 (3.00 g,11.1 mmol) was dissolved in 1, 4-dioxane (50 mL), followed by the addition of pinacol biborate (4.23 g,16.6 mmol), the mixture was degassed and purged 3 times with nitrogen, followed by the addition of potassium acetate (3.27 g,33.3 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (813 mg,1.10 mmol). The mixture was stirred at 100℃for 12 hours under nitrogen atmosphere. TLC monitored no starting material remained. The solvent was then removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate B (2.10 g, yield 60%).
Synthesis of end product compound 6:
6a (120 mg,0.37 mmol) was dissolved in dioxane (5 mL) and water (1 mL), followed by 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), and stirring of the whole system at 80℃for 1 hour, with no starting material remaining as monitored by TLC. To the reaction solution was added water (20 mL), 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 the crude product was separated and purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 6 (19 mg, yield 12%). MS m/z (ESI): 439.1[ M+1]
1 H NMR(400MHz,CD 3 OD)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).
Example 7:
synthesis of intermediate 7 a:
5-bromobenzothiophene (0.60 g,2.82 mmol) was dissolved in tetrahydrofuran (18 mL), LDA (2M, 4.2 mL) was slowly added dropwise at-70℃under nitrogen, and stirred at-70℃for 1 hour. Methyl iodide (800 mg,5.40 mmol) was then added and stirred at-70℃for 2 hours, then warmed to room temperature and stirred for 13 hours. TLC monitored that no starting material remained, adding 30mL of water to quench the reaction, extracting with dichloromethane (30 ml×3), combining the organic phases, washing with saturated aqueous sodium chloride (30 ml×2), drying over anhydrous sodium sulfate, removing the solvent under reduced pressure, and separating and purifying the crude product by thin layer chromatography (ethyl acetate: methanol=20:1) to afford intermediate 7a (0.55 g, 86% yield).
Synthesis of intermediate 7 b:
intermediate 7a (0.55 g,2.38 mmol) was dissolved in dichloromethane (20 mL) and then 1, 1-dichloromethyl ether (319 mg,3.48 mmol) and titanium tetrachloride (480 mg,3.48 mmol) were added under an ice-water bath and stirred at room temperature for 2 hours, with no starting material remaining as monitored by TLC. To the reaction solution was added water (30 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=30:1 to 10:1) to give intermediate 7b (0.50 g, yield 82%).
Synthesis of intermediate 7 c:
intermediate 7b (0.50 g,1.96 mmol) was dissolved in dichloromethane (20 mL), followed by dimethylamine hydrochloride (479 mg,5.80 mmol) and triethylamine (595 mg,5.80 mmol), stirred at room temperature for 5 hours, followed by sodium borohydride acetate (2.49 g,11.7 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was added water (30 mL), extracted with dichloromethane (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 7c (360 mg, yield 65%).
Synthesis of intermediate C:
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), triphenylphosphine (27.5 g,104.7 mmol) were dissolved in tetrahydrofuran (70 mL), and diisopropyl azodicarboxylate (21.2 g,104.7 mmol) was added at 0deg.C under nitrogen. The system was left to react at room temperature for 12 hours, and TLC monitored no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=10:1) to give intermediate C1 (12.0 g, 70% yield).
Intermediate C1 (2.00 g,6.1 mmol) and pinacol biborate (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 is reacted at 100 ℃ for 12 hours under the protection of nitrogen. TLC monitored no starting material remained. Water (50 mL) was added to the system, dichloromethane extraction (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate=10:1) to give intermediate C (2.00 g, yield 61%).
Synthesis of end product compound 7:
intermediate 7C (316 mg,0.84 mmol) was dissolved in dioxane (6 mL) and water (1 mL), followed by 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), degassing of the mixture and purging with nitrogen 3 times, then stirring at 100 ℃ for 3 hours under nitrogen atmosphere, TLC monitoring the starting material for no residue. To the reaction solution was added water (20 mL), 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 the crude product was separated and purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 7 (87 mg, yield 27%). MS m/z (ESI): 452.2[ M+1]
1 H NMR(400MHz，CD 3 OD)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).
Example 8:
synthesis of intermediate 8 a:
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), 4-dimethylaminopyridine (5.63 g,46.0 mmol) was added thereto, stirred under nitrogen atmosphere at room temperature for 20 minutes, then heated to 125℃and stirred for 15 hours, and the TLC monitored material was free. The residue was poured into water (50 mL) and stirred for 5 min, and the mixture was filtered to give intermediate 8a (3.10 g, crude), which was used in the next reaction without purification.
Synthesis of intermediate 8 b:
intermediate 8a (3.10 g, crude) was dissolved in 10mL of dichloromethane, and N-bromosuccinimide (2.90 g,16.3 mmol) and benzoyl peroxide (263 mg,1.00 mmol) were added. The mixture was stirred under nitrogen at room temperature for 12 hours, and TLC monitored no starting material remained. The residue was poured into water (30 mL) and stirred for 3 min, extracted with ethyl acetate (20 ml×3), the combined organic phases were washed with saturated sodium chloride (20 ml×3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 8b (1.30 g, crude), which was used in the next reaction without further purification.
Synthesis of intermediate 8 c:
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. The mixture was stirred under nitrogen at room temperature for 12 hours, and TLC monitored no starting material remained. The pH of the mixture was adjusted to 9 by the addition of saturated sodium bicarbonate, the residue was poured into water (60 mL), stirred for 3 minutes, extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, washed with saturated aqueous sodium chloride (30 mL. Times.3), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate 8c (1.14 g, 34% yield).
Synthesis of intermediate 8 d:
intermediate 8C (0.10 g,0.30 mmol) was dissolved in 1, 4-dioxane (3 mL) and water (0.3 mL), followed by addition of 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). Stirring was carried out at 100℃for 3 hours, and TLC monitored no starting material remained. To the reaction solution was added water (10 mL), extracted with ethyl acetate (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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 8d (130 mg, yield 86%).
Synthesis of end product compound 8:
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 0deg.C. The mixture was stirred at 25 ℃ for 2 hours and TLC detected complete reaction. Ethyl acetate (2 mL) and sodium sulfate (5.00 g) were added to the mixture, and stirred for 5 minutes. Saturated aqueous sodium bicarbonate (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 give a residue which was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give the final product compound 8 (24 mg, yield 32%). MS m/z (ESI): 468.2[ M+1]
1 H NMR(400MHz，CD 3 OD)δ7.88(s,1H),7.80(d,J＝8.4Hz,1H),7.38(d,J＝8.2Hz,1H),7.23-7.11(m,3H),4.91(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).
Example 9:
synthesis of intermediate 9 a:
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 ℃ for 12 hours, and TLC monitored no starting material remained. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was added to 1M HCl to ph=7, the mixture was filtered, and the filter cake was concentrated under reduced pressure to give intermediate 9a (220 mg, crude), which was used without further purification.
Synthesis of intermediate 9 b:
intermediate 9a (210 mg, crude) was dissolved in N, N-dimethylformamide (6 mL), followed by HATU (3831 mg,1.0 mmol) and dimethylamine hydrochloride (164 mg,2.00 mmol), triethylamine (406 mg,4.00 mmol). The mixture was stirred at 20 ℃ for 1 hour, and TLC monitored no starting material remained. The reaction was quenched with ice water solution of saturated sodium bicarbonate (20 mL), extracted with dichloromethane (10 ml×3), the combined organic phases washed with saturated aqueous sodium chloride (10 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate 9b (210 mg, crude) as a yellow solid which was used directly.
Synthesis of intermediate 9 c:
intermediate 9b (200 mg, crude) was dissolved in THF (3 mL) and diisobutylaluminum hydride (1 m,1.8 mL) was added. The mixture was stirred at 20 ℃ for 2 hours, and TLC monitored no starting material remained. The reaction was quenched by addition of an ice water solution of saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium chloride (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford intermediate 9c (182 mg, crude) which was used directly without further purification.
Synthesis of end product compound 9:
intermediate 9C (180 mg, crude), 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 3 times with nitrogen, then the mixture was stirred under nitrogen at 100 ℃ for 3 hours, TLC monitored no starting material remained. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Purification by column chromatography (dichloromethane: methanol=50:1-15:1) afforded compound 9 (44 mg, yield 11%). MS m/z (ESI) 495.2[ M+1]
1 H NMR(400MHz，CD 3 OD)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).
Example 10:
synthesis of intermediate 10 a:
intermediate 8c (250 mg,0.76 mmol) was dissolved in a methanol solution of dimethylamine (6 ml,2 m) and stirred at 100 ℃ for 12 hours, with no starting material remaining as monitored by TLC. The reaction mixture was concentrated under reduced pressure to remove the solvent to give intermediate 10a (235 mg, crude), which was used without further purification.
Synthesis of end product compound 10:
intermediate 10a (235 mg, crude), 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 3 times with nitrogen, then the mixture was stirred under nitrogen atmosphere at 100 ℃ for 3 hours. TLC monitored no starting material remained. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Column chromatography separation and purification (dichloromethane: methanol=30:1-20:1) gave compound 10 (98 mg, 27% yield in two steps). MS m/z (ESI): 509.2[ M+1]
1 H NMR(400MHz，CDCl 3 )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).
Example 11:
synthesis of intermediate 11 a:
(5-bromo-1-benzothien-2-yl) boronic acid (0.70 g,2.70 mmol) was dissolved in 1, 4-dioxane (20 mL), followed by the addition of elemental iodine (622 mg,2.40 mmol) and potassium fluoride (475 mg,8.20 mmol). The mixture was stirred at 80 ℃ for 4 hours, and TLC monitored no starting material remained. The mixture was poured into saturated aqueous sodium sulfite solution (30 mL), 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, then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether) to give intermediate 11a (0.60 g, yield 65%).
Synthesis of intermediate 11 b:
intermediate 11a (0.30 g,0.88 mmol) was dissolved in methanol (10 mL), followed by 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), displacement with nitrogen was performed three times, and the whole system was left under nitrogen atmosphere and stirred at 60℃for 3 hours, with no residual starting material monitored by TLC. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether) to give intermediate 11b (150 mg, yield 70%).
Synthesis of intermediate 11 c:
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 an ice-water bath and stirred at room temperature for 2 hours, and TLC detection was complete. To the reaction solution was added water (30 mL), extracted with dichloromethane (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to give intermediate 11c (180 mg, crude product). The reaction mixture was used in the next reaction without purification.
Synthesis of intermediate 11d
Intermediate 11c (180 mg, crude) was dissolved in 1, 2-dichloroethane (10 mL), followed by the addition of dimethylamine hydrochloride (162 mg,1.90 mmol), 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, and TLC monitored no starting material remained. To the reaction solution was added water (20 mL), 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 then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate: ammonia=1:1:0.01) to give intermediate 11d (100 mg, two-step yield 50%).
Synthesis of end product Compound 11
To intermediate 11d (100 mg,0.33 mmol) 1, 4-dioxane (3 mL) and water (0.3 mL) was added 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 three times with nitrogen, the reaction was allowed to react at 100 ℃ for 3 hours, and TLC monitored no starting material remained. 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 give compound 11 (64 mg, yield 38%). MS m/z (ESI): 468.2[ M+1].
1 H NMR(400MHz,CD 3 OD)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).
Example 12:
synthesis of intermediate 12 a:
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℃for 2 hours. TLC monitored no starting material remained. The reaction mixture was poured into saturated aqueous sodium bicarbonate (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, then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0-0:1) to give intermediate 12a (400 mg, yield 64%).
Synthesis of intermediate 12 b:
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℃for 0.5 h. Acetic acid (98 mg,1.63 mmol) and sodium borohydride (693 mg,3.20 mmol) were added to the mixture. The mixture was stirred at 15℃for 2 hours. TLC monitored no starting material remained. To the reaction solution was added water (20 mL), extracted with dichloromethane (20 ml×3), the organic phases were combined, washed with saturated sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=1:0-0:1) to give intermediate 12b (200 mg, yield 62%).
Synthesis of intermediate 12 c:
intermediate 12b (60 mg,0.15 mmol) was dissolved in dimethyl sulfoxide (5 mL) and under nitrogen, trifluoromethyl trimethylsilane (65 mg,0.45 mmol), cuprous iodide (43 mg,0.23 mmol) and potassium fluoride KF (27 mg,0.45 mmol) were added. The system was stirred at 100℃for 0.5 h. TLC monitored no starting material remained. To the reaction solution was added water (20 mL), 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 then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1) to give intermediate 12c (120 mg, yield 47%).
Synthesis of end product compound 12:
intermediate 12C (70 mg,0.21 mmol) was dissolved in a mixed solution of 1, 4-dioxane (6 mL) and water (1 mL), followed by addition of 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). The mixture was degassed and purged 3 times with nitrogen, then the mixture was stirred under nitrogen atmosphere at 100 ℃ for 3 hours. TLC monitored no starting material remained. 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 give compound 12 (80 mg, yield 77%). MS m/z (ESI) 506.2[ M+1].
1 HNMR(400MHz，CD 3 OD)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).
Example 13:
synthesis of intermediate 13 a:
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 ethyl 2-sulfate (2.92 g,27.5 mmol) and then 4-dimethylaminopyridine (8.41 g,68.8 mmol) in one portion under nitrogen. The whole system was stirred at 125 ℃ for 12 hours and TLC monitored no starting material remained. To the reaction solution was added (50 mL of water) and stirred for 5 minutes. Filtration gave intermediate 13a (2.10 g, 53% yield).
Synthesis of intermediate 13 b:
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 addition of lithium hydroxide monohydrate (616 mg,14.6 mmol) and stirring of the whole system at room temperature for 12 hours, and TLC monitored no starting material remained. The solvent was removed by filtration under reduced pressure, the crude product was poured into water (30 mL), stirred for 5 min, the aqueous phase was extracted with ethyl acetate (20 mL), hydrochloric acid (1M) was added to the aqueous phase to ph=4, the solid was filtered and concentrated in vacuo to afford intermediate 13b (2.08 g, crude).
Synthesis of intermediate 13 c:
intermediate 13b (2.08 g, crude) was dissolved in N-methylpyrrolidone (10 mL) and cuprous oxide (4.37 g,30.5 mmol) was added followed by stirring the whole at 140℃for 12 hours under nitrogen atmosphere and TLC monitored no starting material remained. To the reaction solution was added water (20 mL), 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, followed by column chromatography separation and purification (petroleum ether: ethyl acetate=10:1-5:1) to give intermediate 13c (1.00 g, two-step yield 60%).
Synthesis of intermediate 13d
Intermediate 13c (0.30 g,1.30 mmol) was dissolved in carbon tetrachloride (10 mL) followed by benzoyl peroxide (32 mg,0.13 mmol) and N-bromosuccinimide (234 mg,1.30 mmol), and the whole system was stirred under nitrogen at 80℃for 5 hours, with no starting material remaining as monitored by TLC. The solvent was removed under reduced pressure, water (20 mL), dichloromethane extraction (20 mL. Times.3) was added, the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 13d (465 mg, crude). The reaction mixture was used in the next reaction without purification.
Synthesis of intermediate 13e
Intermediate 13d (465 mg, crude) was dissolved in N, N-dimethylformamide (5 mL), followed by addition of dimethylamine hydrochloride (375 mg,4.50 mmol) and triethylamine (5 mL) and stirring at room temperature for 12 hours, and TLC monitored no starting material remained. The solvent was removed under reduced pressure, water (20 mL) was added, dichloromethane extraction (20 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 the column chromatography was separated and purified (ethyl acetate: methanol: ammonia=10:1:0.05) to give intermediate 13e (170 mg, two-step yield 48%).
Synthesis of end product compound 13:
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), and then 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 added under a nitrogen atmosphere. The mixture was stirred at 100℃for 3 hours. After cooling, the solvent was removed under reduced pressure, water (20 mL) was added, extraction (20 ml×3) was performed with ethyl acetate, 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 the purification (dichloromethane: methanol=20:1) was separated by column chromatography to give compound 13 (55 mg, yield 34%). MS m/z (ESI): 439.2[ M+1]
1 H NMR(400MHz，CD 3 OD)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).
Example 14:
synthesis of intermediate 14 a:
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 ethyl 2-sulfate (1.36 g,12.8 mmol) and then 4-dimethylaminopyridine (3.92 g,32.1 mmol) in one portion under nitrogen. The whole system was stirred at 125 ℃ for 12 hours and TLC monitored no starting material remained. To the reaction solution was added water (50 mL), and stirred for 5 minutes, and then filtered and dried to obtain intermediate 14a (0.68 g, yield 37%).
Synthesis of intermediate 14 b:
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 addition of lithium hydroxide monohydrate (200 mg,4.70 mmol) and stirring of the whole system at room temperature for 12 hours, and TLC monitored no starting material remained. The solvent was removed by filtration under reduced pressure, the crude product was poured into water (30 mL), stirred for 5 min, extracted with ethyl acetate (20 mL), hydrochloric acid (1M) was added to the aqueous phase to ph=4, the solid was filtered and concentrated in vacuo to afford intermediate 14b (0.32 g, crude).
Synthesis of intermediate 14 c:
intermediate 14b (0.27 g,0.99 mmol) was dissolved in N-methylpyrrolidone (10 mL) and under nitrogen followed by addition of cuprous oxide (618 mg,3.90 mmol) and the whole was stirred at 140℃for 12 hours and TLC monitored for no starting material remaining. To the reaction solution was added water (20 mL), 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, followed by column chromatography separation and purification (petroleum ether: ethyl acetate=10:1-5:1) to give intermediate 14c (0.10 g, yield 44%).
Synthesis of intermediate 14 d:
intermediate 14c (0.10 g,0.44 mmol) was dissolved in carbon tetrachloride (5 mL) followed by benzoyl peroxide (11 mg,0.044 mmol) and N-bromosuccinimide (78 mg,0.44 mol) and the whole system was stirred under nitrogen at 80℃for 5 hours, and TLC monitored for the absence of starting material remaining. The solvent was removed under reduced pressure, water (20 mL), dichloromethane extraction (20 mL. Times.3) was added, the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 14d (0.18 g, crude). The reaction mixture was used in the next reaction without purification.
Synthesis of intermediate 14e
Intermediate 14d (0.18 g, crude) 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 stirring at room temperature for 12 hours, TLC monitored no starting material remained. The solvent was removed under reduced pressure, water (20 mL) was added, dichloromethane extraction (10 ml×3), the organic phases were combined, washed with saturated sodium chloride (10 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the column chromatography was separated and purified (ethyl acetate: methanol: ammonia=10:1:0.05) to give intermediate 14e (40 mg, 32% in two steps).
Synthesis of end product compound 14:
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 ] palladium dichloride (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℃for 3 hours. After cooling, the solvent was removed under reduced pressure, water (20 mL) was added, the ethyl acetate extracts (20 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 preparative HPLC (column: phenomenex Luna C, 150 x 30mm x 5um; mobile phase: [ water (0.04% hydrochloric acid) -acetonitrile ];: B%:15% -33%,10 min) to give compound 14 (17 mg, 26% yield). MS m/z (ESI): 439.2[ M+1]
1 H NMR(400MHz,DMSO-d 6 )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).
Example 15:
synthesis of intermediate 15 a:
5-Bromosalicylaldehyde (1.50 g,7.50 mmol) was dissolved in dichloromethane (20 mL), followed by the addition of tetrafluoroboric acid-diethyl ether adduct (0.12 g,0.70 mmol) and then dropwise adding ethyl azoacetate (1.40 g,12.0 mmol) at less than 38deg.C, and the whole system stirred at room temperature for 10min, and TLC monitored no starting material remained. Concentrated under reduced pressure to give a yellow oil. Concentrated sulfuric acid (2.5 mL) was slowly added dropwise to the oil, which was then reacted at room temperature for 10 minutes, and the color became brown. The mixture was diluted with dichloromethane (30 mL), sodium bicarbonate (15.00 g) was added in portions, the whole was stirred at room temperature for 20 hours, and concentrated by filtration to give intermediate 15a (1.90 g, 97% yield) as a yellow oil.
Synthesis of intermediate 15b
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), palladium tetraphenylphosphine (284 mg,0.22 mmol), potassium phosphate trihydrate (1.40 g,4.70 mmol) were added and the system was warmed to 100deg.C under nitrogen protection for 4 hours, with no starting material remaining as monitored by TLC. The system was cooled to room temperature, concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to give intermediate 15b (600 mg, yield 67%).
Synthesis of intermediate 15c
Intermediate 15b (600 mg,2.10 mmol) was dissolved in (25 mL) tetrahydrofuran (25 mL) followed by the addition of lithium aluminum hydride (80 mg,2.10 mmol) and the stirring at room temperature was performed and TLC monitored for no starting material remaining. To the reaction solution was added a little water, followed by addition of silica gel and sample stirring, and the crude product was purified by column chromatography (dichloromethane: methanol=20:1-10:1) to obtain intermediate 15c (250 mg, yield 46%).
Synthesis of intermediate 15d
Intermediate 15c (250 mg,1.00 mmol) was dissolved in dichloromethane (20 mL) followed by addition of phosphorus tribromide (0.15 mL,1.00 mmol) under ice-bath and the system was reacted at room temperature for 3 hours, TLC monitoring the absence of starting material. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (10 mL), the pH was adjusted to be alkaline, the mixture was extracted with dichloro (10 mL. Times.2), the organic phases were combined, washed with saturated sodium chloride (10 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 15d (250 mg, yield 80%).
Synthesis of intermediate 15e
Intermediate 15d (250 mg,0.78 mmol) was dissolved in dichloromethane (25 mL) followed by N, N-diisopropylethylamine (0.2 g,1.5 mmol) and dimethylamine (42 mg,0.94 mmol) and the whole system stirred at room temperature and TLC monitored no starting material remained. The solvent was removed under reduced pressure to give intermediate 15e (150 mg, yield 68%).
Synthesis of end product Compound 15
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 was stirred at 50deg.C and monitored by TLC for the absence of starting material. To the reaction solution was added 50mL of water, 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, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-10:1) to give compound 15 (100 mg, yield 45%). MS m/z (ESI): 422.1[ M+1]
1 H NMR(600MHz，CDCl 3 )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)。
Example 16:
synthesis of intermediate 16 a:
intermediate 1b (300 mg,1.10 mmol) was dissolved in dichloromethane (20 mL), then methylamine hydrochloride (222 mg,2.75 mmol) and triethylamine (333 mg,3.30 mmol) were added, the reaction was stirred at room temperature for 5 hours, then sodium borohydride acetate (706 mg,3.30 mmol) was added, stirring at room temperature overnight, and TLC monitored the starting material for no residue. To the reaction solution was added water (30 mL), 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, followed by column chromatography separation and purification (dichloromethane: methanol=50:1-15:1) to give intermediate 16a (180 mg, yield 57%).
Synthesis of end product compound 16:
intermediate 16a (180 mg,0.63 mmol) was dissolved in N, N-dimethylformamide (10 mL), then intermediate a (213 mg,0.69 mmol) and anhydrous potassium carbonate (214 mg,1.55 mmol) were added, stirred at 50 ℃ for 3 hours, after completion of the reaction, water (30 mL), ethyl acetate extraction (20 ml×3) were added, 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 the mixture was separated and purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give compound 16 (120 mg, yield 45%). MS m/z (ESI) 424.2[ M+1]
1 HNMR(600MHz，CDCl 3 )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).
Example 17:
synthesis of intermediate 17 a:
intermediate 1b (600 mg,2.10 mmol) was dissolved in N, N-dimethylformamide (30 mL), then intermediate a (356 mg,1.16 mmol) and anhydrous potassium carbonate (314 mg,2.27 mmol) were added, the reaction was stirred at 50 ℃ for 3 hours, after the completion of the reaction, water (40 mL) was added to the reaction solution, 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, the solvent was removed under reduced pressure, and the mixture was separated and purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 17a (205 mg, yield 46%).
Synthesis of end product compound 17:
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, then sodium borohydride acetate (350 mg,1.65 mmol), stirred at room temperature overnight, and TLC monitored no starting material remained. To the reaction solution was slowly added water (30 mL), 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, then the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give compound 17 (150 mg, yield 68%). MS m/z (ESI): 444.2[ M+1]
1 H NMR(600MHz，CD 3 OD)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).
Example 18:
synthesis of Compound 18:
compound 16 (100 mg,0.23 mmol) was dissolved in dichloromethane (25 mL), followed by bromoacetonitrile (33 mg,0.28 mmol) and N, N-diisopropylethylamine (61 mg,0.47 mmol) and the system stirred at room temperature for 3 hours and TLC monitored no starting material remained. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (20 mL), extracted with dichloromethane (20 ml×3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=30:1) to give compound 18 (60 mg, yield 56%). MS m/z (ESI): 449.1[ M+1]
1 H NMR(600MHz,CDCl 3 )δ8.00(s,1H),δ7.85(d,J＝8.4Hz,1H),δ7.47(d,J＝
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
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)。
Example 19:
synthesis of Compound 19:
compound 16 (100 mg,0.23 mmol) was dissolved in dichloromethane (25 mL), followed by cyanogen bromide (30 mg,0.28 mmol) and N, N-diisopropylethylamine (61 mg,0.47 mmol) and the system stirred at room temperature for 3 hours and TLC monitored no starting material remained. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (20 mL), extracted with dichloromethane (20 ml×3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=30:1) to give compound 19 (60 mg, yield 57%). MS m/z (ESI): 463.1[ M+1]
1 H NMR(600MHz,CDCl 3 )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)。
Example 20:
synthesis of intermediate 20 a:
5-bromo-3- (chloromethyl) benzothiophene (0.50 g,1.91 mmol) was dissolved in dimethyl sulfoxide (8 mL), followed by slow addition of potassium cyanide (247 mg,3.80 mmol). The reaction was stirred at 25 ℃ for 3 hours, and TLC monitored no starting material remained. Water (20 mL) was added to the reaction system, extracted with ethyl acetate (20 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium chloride (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography (petroleum ether: ethyl acetate=100:1-10:1) afforded intermediate 20a (0.29 g, 60% yield).
Synthesis of intermediate 20 b:
intermediate 20a (200 mg,0.79 mmol) was dissolved in tetrahydrofuran (6 mL) and nickel (23 mg,0.40 mmol) was added under nitrogen. The suspension was degassed under vacuum and purged several times with hydrogen. The mixture was stirred under hydrogen atmosphere at 30 ℃ for 10 hours, TLC monitored no starting material remaining. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 20b (200 mg, crude). The crude product was not further purified.
Synthesis of end product compound 20:
intermediate 20b (150 mg, crude) was dissolved in 1, 4-dioxane (6 mL) and water (1 mL), followed by addition of intermediate C (399mg, 1.00 mmol), potassium carbonate (219 mg,1.58 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (39 mg,0.053 mmol). The mixture was degassed and purged 3 times with nitrogen, then the mixture was stirred under nitrogen for 3 hours at 100 ℃ and TLC monitored no starting material remained. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol=20:1-15:1) to give compound 20 (34 mg, 12% yield in two steps). MS m/z (ESI): 452.2[ M+1]
1 H NMR(400MHz,CDCl 3 ) Delta 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:
Synthesis of intermediate 21 a:
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 monitored no starting material remained. To the reaction solution was added water (50 mL), 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, followed by column chromatography separation and purification (dichloromethane: methanol=30:1-20:1) to give intermediate 21a (300 mg, yield 68%).
Synthesis of intermediate 21 b:
intermediate 21a (300 mg,1.06 mmol) was dissolved in dioxane (30 mL), followed by addition of 3-fluoro-2-hydroxyphenylboronic acid (200 mg,1.27 mmol), tetrakis triphenylphosphine palladium (61 mg,0.05 mmol) and potassium phosphate (420 mg,1.58 mmol), and displacement with nitrogen three times, the whole system was placed under nitrogen. The system was stirred at 100 ℃ under reflux for 4 hours, and TLC monitored no starting material remained. The reaction solution was concentrated under reduced pressure, and was directly purified by column chromatography (petroleum ether: ethyl acetate=10:1-2:1) to give intermediate 21b (250 mg, yield 75%).
Synthesis of intermediate 21 c:
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 was stirred at 50℃and the TLC monitored for the absence of starting material. To the reaction solution was added water (50 mL), 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, followed by column chromatography separation and purification (dichloromethane: methanol=15:1) to give intermediate 21c (214 mg, yield 60%).
Synthesis of end product compound 21:
intermediate 21c (214 mg,0.47 mmol) was dissolved in tetrahydrofuran (10 mL) and deuterated lithium aluminum hydride (60 mg,1.41 mmol) was slowly added at-20℃and the whole system was warmed to 0℃and stirred overnight with no starting material remaining as monitored by TLC. Ice water (20 mL) was added to the reaction solution, extraction was performed 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 purification was performed by column chromatography (dichloromethane: methanol=20:1) to give compound 21 (89 mg, yield 43%). MS m/z (ESI) 440.2[ M+1]
1 H NMR(600MHz，CD 3 OD)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).
Example 22:
synthesis of intermediate 22 a:
Intermediate 1b (0.30 g,1.10 mmol) was dissolved in dichloromethane (50 mL), followed by the addition of two drops of concentrated hydrochloric acid, after 30 minutes by the addition of tetrahydropyrrole (0.157 g,2.20 mmol) the whole system was stirred at room temperature for 5 hours, then sodium borohydride acetate (0.71 g,3.3 mmol) was added and reacted overnight at room temperature, and TLC monitored no starting material remained. Water (50 mL) was added to the reaction solution, extraction was performed with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=50:1-15:1) to give intermediate 22a (0.30 g, yield 86%)
Synthesis of end product 22:
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 entire system was stirred at 50deg.C and the TLC monitored for starting material did not remain. To the reaction solution was added water (50 mL), 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, and purified by column chromatography (dichloromethane: methanol=20:1) to give compound 22 (400 mg, yield 92%). MS m/z (ESI): 464.2[ M+1]
1 H NMR(600MHz，CDCl 3 )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).
Example 23:
synthesis of intermediate 23 a:
intermediate 1b (0.30 g,1.10 mmol) was dissolved in dichloromethane (50 mL), azetidine hydrochloride (206 mg,2.20 mmol) and triethylamine (0.33 g,3.30 mmol) were added and the whole system was stirred at room temperature for 5 hours, then sodium borohydride acetate (0.71 g,3.30 mmol) was added and reacted overnight at room temperature, and TLC monitored the starting material was not left. Water (50 mL) was added to the reaction solution, extraction was performed with methylene chloride (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was separated and purified by column chromatography (methylene chloride: methanol=20:1) to give intermediate 23a (327 mg, yield 95%)
Synthesis of end product compound 23:
intermediate 23a (227 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 was stirred at 50deg.C and monitored by TLC for the absence of starting material. To the reaction solution was added water (50 mL), extracted with dichloromethane (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, and purified by column chromatography (dichloromethane: methanol=20:1) to give compound 23 (400 mg, yield 82%). MS m/z (ESI) 450.2[ M+1].
1 H NMR(600MHz，CD 3 Cl)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),δ3.51(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).
Example 24:
synthesis of intermediate 24 a:
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 oxidant (3.03 g,7.10 mmol) was added at 0deg.C. The mixture was stirred at 15 ℃ for 2 hours, and TLC monitored no starting material remained. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (30 mL) and stirred for 0.5 h. Dichloromethane extraction (30 mL x 2), combined organic phases, dried over anhydrous sodium sulfate, filtration and concentration under reduced pressure, column chromatography separation and purification (petroleum ether: ethyl acetate=50:1-3:1) afforded intermediate 24a (0.53 g, 55% yield).
Synthesis of intermediate 24 b:
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 ℃ for 10 hours, and TLC monitored no starting material remained. Water (5 mL) was added to the system to quench, and the solvent was removed under reduced pressure to give 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 give intermediate 24b (80 mg, yield 12%).
Synthesis of end product compound 24:
compound 24B (80 mg,0.25 mmol) was dissolved in dioxane (3 mL) and water (0.3 mL), 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 three times with nitrogen. The mixture was stirred at 100 ℃ for 10 hours, and TLC monitored no starting material remained. The mixture was filtered and the filtrate concentrated in vacuo to give 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]
1 H NMR(600MHz,CDCl 3 ) Delta 7.94-7.81 (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=7.2 hz, 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=7.2 hz, 2H), 2.29 (s, 6H), 2.03 (s, 3H), 1.85 (s, 3H). Example 25:
synthesis of intermediate 25 a:
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 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 ℃ for 24 hours, and TLC monitored no starting material remained. 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 give intermediate 25a (0.50 g, yield 16%).
Synthesis of intermediate 25 b:
trimethylsulfoxide iodide (740 mg,3.40 mmol) was dissolved in dimethyl sulfoxide (10 mL), and sodium hydride (125 mg,3.10mmol,60% content) was added under nitrogen at 0deg.C. The mixture was stirred at 20℃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 ℃ under nitrogen. The mixture was stirred at 20 ℃ for 10 hours, and TLC monitored no starting material remained. To the reaction solution was added water (30 mL), 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, followed by column chromatography separation and purification (ethyl acetate: methanol=20:1) to give intermediate 25b (0.30 g, yield 56%).
Synthesis of intermediate 25 c:
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 0deg.C under nitrogen. The mixture was stirred at 20 ℃ for 3 hours, and TLC monitored no starting material remained. To the mixture was added ethyl acetate (10 mL), followed by sodium sulfate (10 g), water (0.1 mL) and saturated sodium bicarbonate (0.1 mL) and stirred for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 25c (0.40 g, crude). It was used directly in the next step without purification.
Synthesis of intermediate 25 d:
intermediate 25c (0.25 g,1.40 mmol) was dissolved in dichloromethane (10 mL), followed by triethylamine (426 mg,4.20 mmol) and methanesulfonyl chloride (318 mg,2.80 mmol) was added dropwise to the mixture at 0deg.C. The mixture was stirred at 25 ℃ for 2 hours, and TLC monitored no starting material remained. 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 give intermediate 25d (0.40 g, crude). It was used directly in the next step without purification.
Synthesis of intermediate 25 e:
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 ℃ for 3 hours, TLC monitored no starting material remained. To the reaction solution was added water (50 mL), 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, followed by column chromatography separation and purification (ethyl acetate: methanol=30:1) to give intermediate 25e (250 mg, yield 44%).
Synthesis of end product compound 25:
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), and 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 ℃ for 3 hours, and TLC monitored no starting material remained. The mixture was filtered, and the filtrate was concentrated under reduced pressure, and prepared by column chromatography (dichloromethane-dichloromethane: methanol=20:1) to give compound 25 (35 mg, yield 24%). MS m/z (ESI): 464.2[ M+1]
1 H NMR(400MHz,CD 3 OD)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).
Example 26:
synthesis of intermediate 26 a:
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-bromobutanediamide (2.79 g,15.7 mmol). The mixture was stirred at room temperature for 2 hours, LCMS showed the desired quality was detected. The mixture was concentrated in vacuo. The crude intermediate 26a (3.10 g, crude) was obtained as a brown oil.
Synthesis of intermediate 26 b:
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' -tetramethylurea 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 no starting material remained. The mixture was poured into water (90 mL) and stirred for 5 minutes. The reaction mixture was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium chloride (50 mL). The organic phase was separated, washed with saturated aqueous ammonium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford intermediate 26b (6.50 g, crude). The residue was used directly without further purification.
Synthesis of intermediate 26 c:
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 ℃ for 3 hours, and TLC monitored no starting material remained. The reaction mixture was concentrated under reduced pressure, water (50 mL), ethyl acetate extracts (50 ml×3), the combined organic phases were 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 (petroleum ether: ethyl acetate=5:1-0:1) to give intermediate 26c (1.10 g, yield 19%).
Synthesis of intermediate 26 d:
intermediate 26c (1.10 g,5.50 mmol) was dissolved in dioxane (10 mL) and water (1 mL), followed by the addition of potassium vinyltrifluoroborate (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 3 times with nitrogen, then the mixture was stirred at 110 ℃ for 12 hours under nitrogen atmosphere, LCMS showed the desired mass was detected. To the mixture was added water (30 mL), 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 give intermediate 26d (0.70 g, yield 86%).
Synthesis of intermediate 26 e:
intermediate 26d (0.70 g,4.70 mmol) was dissolved in dioxane (20 mL) and 9-borobicyclo [3.3.1] nonane (0.5M in tetrahydrofuran, 19.0 mL) was added under nitrogen. The mixture was heated to 100 ℃ and stirred for 10 hours. The mixture was cooled to 20deg.C, and ethanol (2.19 g,47.5 mmol) and sodium hydroxide (6M, 1.3 mL) were added to the mixture. The mixture was stirred for 30 minutes, and then hydrogen peroxide (944 mg,8.30mmol,30% purity) was added dropwise. The mixture was stirred at 80 ℃ for 2 hours, LCMS showed the reaction was complete. To the reaction solution was added saturated aqueous sodium sulfite solution (20 mL), extracted with ethyl acetate (30 ml×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography separation and purification (petroleum ether: ethyl acetate=5:1-0:1) afforded intermediate 26e (0.75 g, 96% yield).
Synthesis of intermediate 26 f:
intermediate 26e (150 mg,0.91 mmol) was dissolved in tetrahydrofuran (5 mL), followed by triphenylphosphine (719mg, 2.70 mmol) and 2-bromo-6-fluorophenol (349 mg,1.80 mmol) and diisopropyl azodicarboxylate (553mg, 2.70 mmol) at 0deg.C was added and the mixture was heated to 40deg.C and stirred for 10 hours, and TLC monitored for starting material no residue. Concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate 26f (180 mg, yield 59%).
Synthesis of end product compound 26:
intermediate 26f (180 mg,0.53 mmol) was dissolved in dioxane (8 mL) and water (1 mL), followed by 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 3 times with nitrogen, then the mixture was stirred at 100 ℃ under nitrogen for 10 hours, TLC monitored no starting material remained. The reaction solution was filtered and concentrated under reduced pressure, and purified by column chromatography (dichloromethane-dichloromethane: methanol=20:1) to give compound 26 (20 mg, yield 17%). MS m/z (ESI): 449.2[ M+1]
1 H NMR(400MHz,CD 3 OD)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).
Example 27:
synthesis of intermediate 27 a:
intermediate 26 (100 mg,0.22 mmol) was dissolved in tetrahydrofuran (5 mL) and lithium aluminum hydride (17 mg,0.45 mmol) was added at 0deg.C. The mixture was stirred at 75 ℃ for 3 hours, and TLC monitored no starting material remained. Quench the reaction with water (5 mL) and concentrate the reaction mixture under reduced pressure to remove the solvent to give intermediate 27a (80 mg, crude) which is used in the next step without further purification.
Synthesis of end product compound 27:
intermediate 27a (80 mg, crude) was dissolved in dichloromethane (5 mL), followed by triethylamine (90 mg,0.88 mmol), acetyl chloride (28 mg,0.35 mmol) was added dropwise at 0 ℃, and the mixture was stirred at 20 ℃ for 2 hours, with no starting material remaining as monitored by TLC. The solvent was removed by concentration under reduced pressure, and purification by column chromatography (dichloromethane-dichloromethane: methanol=20:1) gave compound 27 (29 mg, 27% yield over 2 steps). MS m/z (ESI) 495.2[ M+1]
1 H NMR(400MHz,CD 3 OD)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).
Example 28:
synthesis of Compound 28:
intermediate 27a (100 mg,0.22 mmol) was dissolved in dichloromethane (5 mL), followed by triethylamine (0.3 mL) and methanesulfonyl chloride (51 mg,0.04 mmol) was added dropwise at 0 ℃ and the mixture was stirred at 20 ℃ for 2 hours. TLC showed complete consumption of starting material. The solvent was removed by concentration under reduced pressure, and purified by column chromatography (dichloromethane-dichloromethane: methanol=20:1) to give compound 28 (31 mg, yield 26%). MS m/z (ESI): 531.2[ M+1]
1 H NMR(400MHz,CD 3 OD)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).
Example 29:
synthesis of intermediate 29 a:
ethyl 1, 5-dimethylpyrazole-3-carboxylate (10.00 g,58.27 mmol) was dissolved in 1, 2-dichloroethane (100 mL), followed by N-bromobutanediamide (20.74 g,116.5 mmol) and stirred at 80℃under nitrogen for 16 h. The mixture was cooled to 25 ℃. Water (200 mL) was added to the system, dichloromethane extraction (200 mL. Times.3), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, column chromatography separation and purification (petroleum ether: ethyl acetate=1:1) gave intermediate 29a (11.0 g, yield 75%).
Synthesis of intermediate 29 b:
intermediate 29a (10.00 g,39.66 mmol) was dissolved in a solution of ethylene glycol dimethyl ether (400 mL) and water (40 mL) at room temperature under nitrogen followed by the addition of (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 ] palladium dichloride (1.45 g,1.98 mmol). The resulting mixture was stirred at 90 ℃ under nitrogen atmosphere for 16 hours. The mixture was cooled to 25 ℃. Water (500 mL) was added to the reaction system, extraction was performed with ethyl acetate (500 mL. Times.3), washing was performed with saturated sodium chloride (300 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (petroleum ether: ethyl acetate=5:1), to give intermediate 29b (5.00 g, yield 52%).
Synthesis of intermediate 29 c:
intermediate 29b (4.50 g,18.51 mmol) was dissolved in tetrahydrofuran (45 mL) and hydrochloric acid (6M, 30 mL) was added dropwise at 0deg.C. The resulting mixture was stirred at 25 ℃ for 3 hours, and TLC monitored no starting material remained. Water (150 mL) was added to the reaction system, extraction was performed with ethyl acetate (150 mL. Times.3), washing was performed with saturated sodium chloride (100 mL. Times.2), drying was performed with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain intermediate 29c (4.00 g, yield 92%).
Synthesis of intermediate 29 d:
intermediate 29c (4.00 g,17.12 mmol) was dissolved in ethanol (40 mL) and sodium borohydride (1.62 g,42.82 mmol) was added in portions at 0deg.C. The resulting mixture was stirred at 25 ℃ for 1 hour, and TLC monitored no starting material remained. Water (150 mL) was added to the reaction system, extraction was performed with ethyl acetate (150 mL. Times.3), washing was performed with saturated sodium chloride (100 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (petroleum ether: ethyl acetate=1:1), to give intermediate 29d (2.50 g, yield 67%).
Synthesis of intermediate 29 e:
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 0deg.C. The resulting mixture was stirred at 25 ℃ for 2 hours, and TLC monitored no starting material remained. Water (50 mL) was added to the reaction system, dichloromethane extraction (50 mL. Times.3), washing with saturated sodium chloride (40 mL. Times.2), drying over anhydrous sodium sulfate, and removal of the solvent under reduced pressure gave intermediate 29e (1.20 g, yield 81%).
Synthesis of end product compound 29:
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 (264 mg,1.12 mmol) and stirring at 100deg.C under nitrogen for 16 hours, TLC monitored no starting material remained. The mixture was cooled to 25 ℃. Water (30 mL) was added to the reaction system, extraction was performed with ethyl acetate (30 mL. Times.3), washing was performed with saturated sodium chloride (20 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (petroleum ether: ethyl acetate=1:1), whereby compound 29 (100 mg, yield 53%) was obtained. MS (m/z, ESI): 496.2[ M+1]
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)。
Example 30:
synthesis of Compound 30:
compound 29 (1.00 g,1.98 mmol) was dissolved in tetrahydrofuran (20 mL) and lithium aluminum hydride (0.79 mL,1.98mmol,2.5M in THF) was added dropwise at 0deg.C. Stirred at 0℃for 1 hour. The reaction was quenched with sodium sulfate decahydrate (2.87 g) at 0 ℃. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (20 ml×3), the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give the final product 30 (94 mg, yield 10%). MS m/z (ESI): 454.2[ M+1]
1 H NMR(400MHz,CDCl 3 )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),7.17-7.05(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).
Example 31:
Synthesis of intermediate 31 a:
compound 30 (550 mg,1.09 mmol) was dissolved in dichloromethane (10 mL), followed by triethylamine (331 mg,3.27 mmol) and methanesulfonyl chloride (188 mg,1.64 mmol) was added dropwise at 0 ℃. The resulting mixture was stirred at 25℃for 30 minutes. Water (50 mL) was added to the reaction system, dichloromethane extraction (50 mL. Times.3), washing with saturated sodium chloride (40 mL. Times.2), drying over anhydrous sodium sulfate, and removal of the solvent under reduced pressure gave intermediate 31a (300 mg, yield 52%).
Synthesis of end product compound 31:
intermediate 31a (300 mg,0.57 mmol) was dissolved in N, N-dimethylformamide (5 mL), followed by the addition of sodium methoxide (117 mg,1.14 mmol) and the solution stirred at 25℃for 24 hours. Water (30 mL) was added to the reaction system, extraction was performed with ethyl acetate (30 mL. Times.3), washing was performed with saturated sodium chloride (20 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (petroleum ether: ethyl acetate=1:1), whereby compound 31 (72 mg, yield 24%) was obtained. MS m/z (ESI): 516.2[ M+1]
1 H NMR(400MHz,CDCl 3 )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).
Example 32:
compound 26 (100 mg,0.22 mmol) was dissolved in water (0.2 mL) and ethanol (2 mL), followed by aldoxime (1 mL), triphenylphosphine (12 mg,0.045 mmol) and palladium acetate (5 mg,0.022 mmol). The resulting mixture was stirred at 80 ℃ for 5 hours, and TLC monitored no starting material remained. 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, 39% yield). MS m/z (ESI): 467.2[ M+1]
1 H NMR(400MHz,CD 3 OD)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,3H),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).
Example 33:
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 monitored no starting material remained. The system was concentrated and the crude product was isolated and purified by thin plate chromatography (dichloromethane: methanol=10:1) to give intermediate 33a (100 mg, 76% yield).
Intermediate 33a (50 mg,0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added, and the system was reacted at room temperature for 10 minutes, followed by dimethylamine hydrochloride (10 mg,0.12 mmol). The reaction system was allowed to react at room temperature for two hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1) to give compound 33 (32 mg, yield 65%). MS (m/z, ESI): 495.2[ M+1]
1 H NMR(400MHz,DMSO-d 6 )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).
Example 34:
intermediate 33a (50 mg,0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added and the system was left to react at room temperature for 10 minutes, followed by the addition of 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride (27 mg,0.12 mmol). The reaction system was allowed to react at room temperature for two hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), whereby compound 34 (40 mg, yield 62%) was obtained. MS (m/z, ESI): 642.2[ M+1]
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)。
Example 35:
compound 29 (100 mg,0.20 mmol) was dissolved in methanol (1 mL) and tetrahydrofuran (1 mL), aqueous hydroxylamine solution (50%, 133mg,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 monitored no starting material remained. The reaction system was concentrated, and the crude product was separated and purified by thin plate chromatography (dichloromethane: methanol=10:1) to give compound 35 (40 mg, yield 41%). MS (m/z, ESI): 483.2[ M+1]
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).
Example 36:
intermediate 33a (50 mg,0.10 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added and the system was reacted at room temperature for 10 minutes, morpholine (26 mg,0.30 mmol) was added. The reaction system was allowed to react at room temperature for 2 hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1) to give compound 36 (30 mg, yield 53%). MS (m/z, ESI): 537.2[ M+1]
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).
Example 37:
intermediate 33a (50 mg,0.10 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added and the system was reacted at room temperature for 10 min and aniline (28 mg,0.30 mmol) was added. The reaction system was allowed to react at room temperature for 2 hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), whereby compound 37 (30 mg, yield 56%) was obtained. MS (m/z, ESI): 543.2[ M+1]
1 H 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,3H),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).
Example 38:
intermediate 33a (50 mg,0.10 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added and the system was left to react at room temperature for 10 minutes, followed by addition of 2-aminopyridine (28 mg,0.30 mmol). The reaction system was allowed to react at room temperature for 2 hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), whereby compound 38 (20 mg, yield 37%) was obtained. MS (m/z, ESI): 543.2[ M+1]
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＝1.2Hz,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).
Example 39:
intermediate 33a (50 mg,0.10 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added and the system was left to react at room temperature for 10 minutes, followed by addition of 3-aminopyrazole (25 mg,0.30 mmol). The reaction system was allowed to react at room temperature for 2 hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), whereby compound 39 (25 mg, yield 47%) was obtained. MS (m/z, ESI): 533.2[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 40:
intermediate 33a (50 mg,0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added, and the system was reacted at room temperature for 10 minutes, followed by addition of methylamine hydrochloride (9 mg,0.12 mmol). The reaction system was allowed to react at room temperature for two hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), whereby compound 40 (30 mg, yield 65%) was obtained. MS (m/z, ESI): 481.2[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 41:
intermediate 33a (50 mg,0.1 mmol) was dissolved in N, N-dimethylformamide (2 mL), triethylamine (20 mg,0.2 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (50 mg,0.13 mmol) were added, and the system was reacted at room temperature for 10 minutes, followed by aminoacetonitrile (7 mg,0.12 mmol). The reaction system was allowed to react at room temperature for two hours. TLC monitored no starting material remained. Water (10 mL) was added to the reaction system, extraction was performed with ethyl acetate (10 mL. Times.3), washing was performed with saturated sodium chloride (10 mL. Times.2), drying was performed over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1) to give compound 41 (32 mg, yield 63%). MS (m/z, ESI): 506.2[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 42:
synthesis of intermediate 42 a:
33a (200 mg,0.43 mmol) was dissolved in N, N-dimethylformamide (5 mL), triethylamine (87 mg,0.86 mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (212 mg,0.56 mmol) were added, and the system was left to react at room temperature for 10 minutes, followed by addition of Boc-glycine (67 mg,0.51 mmol). The reaction system was allowed to react at room temperature for 2 hours. TLC monitored no starting material remained. Water (20 mL) was added to the reaction system, extraction was performed with ethyl acetate (20 mL. Times.3), washing was performed with saturated sodium chloride (20 mL. Times.2), drying was performed with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification was performed by column chromatography (dichloromethane: methanol=10:1), to give 42a (160 mg, yield 64%).
Synthesis of end product 42:
42a (160 mg,0.27 mmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (4 mL) was added. The system was allowed to react overnight at room temperature. TLC monitored no starting material remained. The solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=10:1) to give final product 42 (70 mg, yield 50%). MS (m/z, ESI): 525.2[ M+1]
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).
Example 43:
synthesis of intermediate 43a
3-fluoro-2-hydroxyphenylboronic acid (300 mg,1.92 mmol) was dissolved in dioxane (30 mL), followed by addition of 7b (400 mg,1.57 mmol), tetrakis triphenylphosphine palladium (127 mg,0.10 mmol) and potassium phosphate (837 mg,3.14 mmol), and displacement with nitrogen three times, the whole system was put under nitrogen. The system was stirred at 100 ℃ under reflux for 4h, and no starting material remained as monitored by tlc. The reaction solution was directly purified by column chromatography (petroleum ether: ethyl acetate=10:1-2:1) to give 43a (380 mg, yield 84%). MS m/z (ESI): 286.9[ M+1]
Synthesis of intermediate 43b
43a (380 mg,1.33 mmol) was dissolved in methanol (30 mL), followed by the addition of methylamine hydrochloride (178 mg,2.66 mmol), triethylamine (335 mg,3.32 mmol), the whole was reacted at room temperature for 2h, naBH was applied 4 (101 mg,2.66 mmol) was added to the reaction solution, and stirring was continued for 1h. TLC detection showed no starting material remaining. 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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1-1:2) to give 43b (200 mg, yield 50%). MS m/z (ESI): 301.9[ M+1]]
Synthesis of intermediate 43c
43b (200 mg,0.66 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by intermediate A (290 mg,0.80 mmol) and potassium carbonate (182 mg,1.32 mmol) and the whole system was stirred at 60℃and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1-15:1) to give 43c (150 mg, yield 46%). MS m/z (ESI): 496.2[ M+1]
Synthesis of end product 43
43c (150 mg,0.30 mmol) was dissolved in dry tetrahydrofuran (25 mL) followed by addition of LiAlH 4 (23 mg,0.60 mmol) and the whole system was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (5 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 43 (100 mg, yield 74%). MS m/z (ESI) 454.1[ M+1 ]]
1 H NMR(600MHz,DMSO-d 6 ) Delta 7.93 (s, 1H), 7.90 (d, j=7.8 hz, 1H), 7.41 (dd, 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:
synthesis of intermediate 44a
43a (380 mg,1.33 mmol) was dissolved in methanol (30 mL), followed by the addition of dimethylamine hydrochloride (215 mg,2.66 mmol), triethylamine (335 mg,3.32 mmol), the whole was reacted at room temperature for 2h, naBH was applied 4 (101 mg,2.66 mmol) was added to the reaction solution, and stirring was continued for 1h. TLC detection showed no starting material remaining. 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, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1-1:2) to give 44a (250 mg, yield 60%). MS m/z (ESI): 315.9[ M+1 ] ]
Synthesis of intermediate 44b
44a (250 mg,0.79 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by 29e (276 mg,0.95 mmol) and potassium carbonate (218 mg,1.58 mmol) and the whole system was stirred at 60℃and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), 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, and after purification of the crude product by column chromatography (dichloromethane: methanol=30:1-15:1), 44b (200 mg, yield 50%) was obtained. MS m/z (ESI): 510.2[ M+1]
Synthesis of end product 44
44b (200 mg,0.39 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) followed by addition of LiAlH 4 (30 mg,0.78 mmol) and the whole system was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (5 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 44 (100 mg, yield 55%). MS m/z (ESI) 454.1[ M+1]]
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).
Example 45:
synthesis of intermediate 45 a:
21b (250 mg,0.79 mmol) was dissolved in dry tetrahydrofuran (25 mL) and LiAlD was added 4 (30 mg,1.58 mmol) the whole system was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (5 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1-15:1) to give 45a (150 mg, yield 63%). MS m/z (ESI) 304.1[ M+1]]
Synthesis of intermediate 45 b:
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℃and tracked by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1-15:1) to give 45b (100 mg, yield 40%). MS m/z (ESI): 498.1[ M+1]
Synthesis of end product 45:
45b (100 mg,0.20 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) followed by addition of LiAlH 4 (15 mg,0.40 mmol) the whole system was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (5 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 45 (50 mg, yield 55%). MS m/z (ESI): 456.1[ M+1] ]
1 H 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),7.24-7.18(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).
Example 46:
synthesis of intermediate 46 a:
4-Bromothiophenol (8.00 g,42.8 mmol) was dissolved in methylene chloride (100 mL), and ethyl 4-chloroacetoacetate (7.00 g,42.8 mmol) and triethylamine (6.50 g,63.5 mmol) were added and the whole was stirred at room temperature for 2.5h. 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 give 46a. (12.00 g, 89% yield). MS m/z (ESI): 317.2[ M+1]
Synthesis of intermediate 216 b:
polyphosphoric acid (40.00 g) was added to toluene (100 mL) followed by 46a (12.00 g,38.0 mmol) and the whole was stirred at 100deg.C for 10h. The supernatant of the reaction solution was purified by column chromatography (petroleum ether: ethyl acetate=40:1-20:1) to give 46b. (6.80 g, 60% yield). MS m/z (ESI): 299.2[ M+1]
Synthesis of intermediate 46 c:
46b (6.80 g,22.7 mmol) was dissolved in carbon tetrachloride (100 mL), followed by NBS (4.90 g,27.3 mmol) and benzoyl peroxide (8.0 mg,0.03 mmol) were added and the whole was stirred under reflux for 8h. 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 give 46c. (6.00 g, 70% yield). MS m/z (ESI): 377.2[ M+1]
Synthesis of intermediate 46 d:
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 (267 mg,2.66 mmol), and the whole was stirred at room temperature for 2h, and TLC monitored for no starting material remaining. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1-2:1) to give 46d (350 mg, yield 77%). MS m/z (ESI): 342.1[ M+1]
Synthesis of intermediate 46 e:
46d (350 mg,1.03 mmol) was dissolved in dioxane (40 mL), followed by addition of 3-fluoro-2-hydroxyphenylboronic acid (192 mg,1.23 mmol), tetrakis triphenylphosphine palladium (83 mg,0.07 mmol) and potassium phosphate (268 mg,2.06 mmol), and displacement with nitrogen three times, the whole system was under nitrogen atmosphere. The system was stirred at 100 ℃ under reflux for 4h, and no starting material remained as monitored by tlc. The reaction solution was directly purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:2) to give 46e (250 mg, yield 65%). MS m/z (ESI): 374.1[ M+1]
Synthesis of intermediate 46 f:
46e (250 mg,0.67 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by addition of A (220 mg,0.67 mmol) and potassium carbonate (185 mg,1.34 mmol), and the whole was stirred at 60℃and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), and the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1-15:1) to give 46f (250 mg, yield 66%). MS m/z (ESI): 568.1[ M+1]
Synthesis of end product 46:
46f (250 mg,0.44 mmol) in also anhydrous tetrahydrofuran (25 mL) was followed by addition of LiAlH 4 (33 mg,0.88 mmol) and the whole system was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 46 (100 mg, yield 47%). MS m/z (ESI) 484.1[ M+1]]
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).
Example 47:
synthesis of intermediate 47 a:
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 (268 mg,2.66 mmol), and the whole was stirred at room temperature for 2h, and TLC monitored the starting material for no residue. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1-2:1) to give 47a (350 mg, yield 81%). MS m/z (ESI): 328.1[ M+1]
Synthesis of intermediate 47 b:
47a (350 mg,1.07 mmol) was dissolved in dioxane (40 mL), followed by addition of 3-fluoro-2-hydroxyphenylboronic acid (200 mg,1.27 mmol), tetrakis triphenylphosphine palladium (61 mg,0.05 mmol) and potassium phosphate (420 mg,1.58 mmol), and the whole system was subjected to nitrogen atmosphere by three times of substitution with nitrogen. The system was stirred at 100 ℃ under reflux for 4h, and no starting material remained as monitored by tlc. The reaction solution was directly purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:2) to give 47b (255 mg, yield 66%). MS m/z (ESI) 360.1[ M+1]
Synthesis of intermediate 47 c:
47b (255 mg,0.71 mmol) was dissolved in N, N-dimethylformamide (40 mL), followed by intermediate A (312 mg,0.85 mmol) and potassium carbonate (196 mg,1.42 mmol) and the whole system was stirred at 60℃and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (dichloromethane: methanol=30:1-15:1) to give 47c (250 mg, yield 64%). MS m/z (ESI): 554.1[ M+1]
Synthesis of end product 47:
47c (250 mg,0.45 mmol) was dissolved in dry tetrahydrofuran (25 mL) followed by addition of LiAlH 4 (34 mg,0.90 mmol) and the whole was stirred at room temperature and monitored by TLC until no starting material remained. To the reaction solution was added water (5 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by preparative plate (dichloromethane: methanol=15:1) to give 47 (115 mg, yield 55%). MS m/z (ESI) 470.1[ M+1]]
1 H 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).
Example 48:
synthesis of end product 48:
43b (200 mg,0.66 mmol) was dissolved in N, N-dimethylformamide (25 mL), followed by intermediate D (290 mg,0.80 mmol) and potassium carbonate (182 mg,1.32 mmol) and the whole system was stirred at 60℃and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), extracted with ethyl acetate (25 ml×2), the organic phases were combined, backwashed with water (25 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 48 (150 mg, yield 46%). MS m/z (ESI): 496.2[ M+1]
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).
Example 49:
synthesis of intermediate 49 a:
48 (500 mg,1.11 mmol) was dissolved in dichloromethane (25 mL) followed by di-tert-butyl dicarbonate (292 mg,1.34 mmol) and triethylamine (224 mg,2.22 mmol) and the whole system stirred at room temperature for 1.5h with TLC monitoring tracking of no starting material remaining. To the reaction solution was added water (50 mL), extracted with dichloromethane (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=10:1-5:1) to give 49 (550 mg, yield 90%). MS m/z (ESI): 549.2[ M+1]
Synthesis of intermediate 49 b:
49a (550 mg,1.00 mmol) was dissolved in methanol (25 mL) followed by the addition of NiCl at 0deg.C 2 ·6H 2 O (15 mg,0.10 mmol) and NaBH 4 (266 mg,7.00 mmol) and the whole was stirred at room temperature for 1.5h, TLC monitoring followed by no starting material remaining. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=30:1-20:1) to give 49b (300 mg, yield 54%). MS m/z (ESI): 553.2[ M+1]]
Synthesis of intermediate 49 c:
49b (300 mg,0.54 mmol) was dissolved in dichloromethane (25 mL) followed by acetic anhydride (110 mg,1.08 mmol) and triethylamine (110 mg,1.08 mmol) and the whole was stirred at room temperature for 1h and TLC monitoring followed by no starting material remaining. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (30 mL), extracted with dichloromethane (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate=5:1-1:1) to give 49c (250 mg, yield 78%). MS m/z (ESI): 595.2[ M+1]
Synthesis of end product 49:
49c (250 mg,0.42 mmol) was dissolved in dichloromethane (25 mL) followed by trifluoroacetic acid (3 mL) and the whole was stirred at room temperature for 1h, and TLC monitoring followed by no starting material remaining. To the reaction solution was added saturated aqueous sodium bicarbonate (25 mL), extracted with dichloromethane (25 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was purified via a preparative plate (dichloromethane: methanol=15:1) to give the final product 49 (100 mg, yield 50%). MS m/z (ESI) 495.2[ M+1]
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),4.00(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).
Example 50:
synthesis of intermediate 50 a:
16a (700 mg,2.44 mmol) was dissolved in N, N-dimethylformamide (10 mL), followed by 29e (0.85 g,2.92 mmol) and potassium carbonate (1.01 g,7.31 mmol) and the whole system stirred at 60℃and reacted for 24h with TLC monitoring and tracking until no starting material remained. To the reaction solution was added water (100 mL), 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, and purified by column chromatography (dichloromethane: methanol=20:1-10:1) to give 50a (825 mg, yield 70%). MS m/z (ESI): 482.2[ M+1]
Synthesis of end product 50:
50a (500 mg,1.09 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) followed by addition of lithium aluminum hydride (207 mg,5.45 mmol) under ice bath, the whole system stirred under ice bath for 20min, and TLC monitoring was followed until no starting material remained. The system was extracted with 10% aqueous sodium hydroxide (50 mL), ethyl acetate (50 ml×3), the organic phases combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, the solvent removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=10:1-5:1) to give the final product 50 (350 mg, yield 77%). MS m/z (ESI) 440.2[ M+1]
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(brs,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).
Example 51:
synthesis of intermediate 51 a:
1a (2.00 g,8.29 mmol) was dissolved in 1, 4-dioxane (20 mL), followed by the addition of pinacol biborate (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), and the displacement with nitrogen was three times, the whole system was left under nitrogen atmosphere, the whole system was stirred for 4h at 100℃and TLC detection of no starting material remained. The reaction was purified by direct column chromatography (ethyl acetate: petroleum ether=1:3) to give 51a (2.10 g, yield 88%). MS m/z (ESI): 289.1[ M+1]
Synthesis of intermediate 51 b:
2-bromo-4, 6-difluorophenol (300 mg,1.44 mmol), 29d (275 mg,1.30 mmol), triphenylphosphine (560 mg,2.16 mmol) were dissolved in anhydrous tetrahydrofuran (5 mL), the whole system was replaced three times with nitrogen, diisopropyl azodicarboxylate (437 mg,2.16 mmol) was added under an ice bath, and the reaction was carried out at room temperature for 1h after the completion of the dropwise addition, and no starting material remained by TLC. The reaction was purified by direct column chromatography (ethyl acetate: petroleum ether=1:3) to give 51b (550 mg, yield 95%). MS m/z (ESI) 402.0[ M+1]
Synthesis of intermediate 51 c:
51a (566 mg,1.97 mmol) was dissolved in 1, 4-dioxane (25 mL), followed by 51b (610 mg,1.51 mmol), tetrakis triphenylphosphine palladium (87 mg,0.08 mmol) and K 3 PO 4 ·3H 2 O (805 mg,3.02 mmol) was replaced with nitrogen three times and the whole was left under nitrogen atmosphere and stirred at 110℃for 4h at room temperature, the TLC detection starting material did not remain. The reaction was purified by direct column chromatography (dichloromethane: methanol=20:1) to give 51c (575 m g, 78% yield). MS m/z (ESI): 485.1[ M+1]]
Synthesis of intermediate 51 d:
51c (575 mg,1.18 mmol) was dissolved in methanol (10 mL), followed by the addition of methylamine hydrochloride (242 mg,3.56 mmol), triethylamine (495 mg,3.56 mmol), the whole system was stirred at room temperature for 2h, followed by the addition of sodium borohydride (90 mg,2.37 mmol), the whole system continued to be stirred at room temperature for 2h, and TLC detection of no starting material remained. Ice water (100 mL) was added to the reaction solution, PH 1-2 was adjusted with hydrochloric acid, ethyl acetate (50 mL), petroleum ether extraction (50 mL), the organic phase was discarded, the aqueous phase was adjusted to PH 8-9 with sodium hydrogencarbonate, ethyl acetate extraction (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 give 51d (84 m g, yield 14%). MS m/z (ESI) 500.2[ M+1]
Synthesis of final product 51:
51d (84 mg,0.17 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) followed by addition of lithium aluminum hydride (13 mg,0.34 mmol) under ice bath, the whole system stirred under ice bath for 20min, and TLC monitoring was followed until no starting material remained. The system was added to ice 10% sodium hydroxide (50 mL), extracted with ethyl acetate (50 ml×3), the organic phases combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, the solvent removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=10:1-5:1) to give the final product 51 (50 mg, 65% yield). MS m/z (ESI) 458.2[ M+1]
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).
Example 52:
synthesis of intermediate 52 a:
50a (500 mg,1.04 mmol) was dissolved in dichloromethane (10 mL), followed by di-tert-butyl dicarbonate (340 mg,3.12 mmol), triethylamine (433 mg,3.12 mmol) and catalytic amount of 4-dimethylaminopyridine, the system was stirred at room temperature for 3h and TLC monitored for no starting material remaining. The reaction was directly purified by column chromatography (dichloromethane: methanol=50:1) to give 52a (539 mg, yield 89%). MS m/z (ESI): 582.2[ M+1]
Synthesis of intermediate 52 b:
52a (520 mg,0.89 mmol) was dissolved in ethanol (5 mL), followed by the addition of sodium hydroxide (143 mg,3.58 mmol) in ethanol (2.5 mL), the whole was stirred at room temperature for 5h, and no starting material remained by TLC. To the reaction solution was added water (100 mL), extracted with ethyl acetate (50 mL), the organic phase was discarded, the aqueous phase was pH-adjusted with hydrochloric acid to 1-2, extracted with ethyl acetate (50 mL. Times.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 give 52b (460 mg, yield 96%). MS m/z (ESI): 552.2[ M-1]
Synthesis of intermediate 52 c:
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-benzotriazol-oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate (129 mg,0.34 mmol) and N, N-diisopropylethylamine (112 uL,0.68 mmol), and the whole system was stirred at room temperature for 5h, and TLC detected no starting material remained. To the reaction solution was added water (100 mL), 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 then the solvent was removed under reduced pressure, and separated and purified by column chromatography (dichloromethane: methanol=50:1-20:1) to give 52c (60 mg, yield 61%). MS m/z (ESI): 581.2[ M+1]
Synthesis of end product 52:
52c (60 mg,0.10 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 2mL of trifluoroacetic acid and the whole was stirred at room temperature for 2h and monitored by TLC until no starting material remained. To the reaction solution was added water (50 mL), sodium hydrogencarbonate was added to adjust PH 8 to 9, 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, the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=20:1 to 5:1) to give a final product 52 (15 mg, yield 37%). MS m/z (ESI): 466.1[ M+1]
1 H 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).
Example 53:
synthesis of intermediate 53 a:
5-bromobenzo [ B ] thiophene-3-carboxylic acid (1.00 g,3.87 mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by 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) were added, the whole was stirred at room temperature overnight and TLC monitored for the absence of starting material. To the reaction solution was added water (100 mL), 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, followed by separation and purification by column chromatography (dichloromethane: methanol=50:1-20:1) to give 1a (0.90 g, yield 80%). MS m/z (ESI): 292.0[ M+1]
Synthesis of intermediate 53 b:
53a (0.90 g,3.08 mmol) was dissolved in ethylene glycol dimethyl ether (30 mL), followed by 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 displacement of the whole system with nitrogen three times under nitrogen atmosphere. The system was stirred at 80 ℃ under reflux and reacted for 4h, with no starting material remaining as monitored by tlc. Concentrated under reduced pressure, and purified by column chromatography (dichloromethane: methanol=50:1-10:1) to give 1b (0.80 g, yield 81%). MS m/z (ESI): 322.1[ M+1]
Synthesis of intermediate 53 c:
53b (0.80 g,2.49 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) followed by the addition of lithium aluminum hydride deuteride (0.21 g,4.98 mmol) under ice water bath and the whole system stirred overnight at room temperature and TLC detection until no starting material remained. To the reaction solution was added water (50 mL), followed by extraction 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, and purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give 1c (0.65 g, yield 84%). MS m/z (ESI): 310.1[ M+1]
Synthesis of intermediate 53 d:
53c (0.650 g,2.10 mmol) was dissolved in N, N-dimethylformamide (30 mL), followed by addition of 29e (0.73 g,2.52 mmol) and anhydrous potassium carbonate (0.58 g,4.20 mmol) and stirring of the whole system at room temperature overnight, TLC monitored the starting material for no residue. MS m/z (ESI): 504.25[ M+1]
Synthesis of end product 53:
53d (0.12 g,0.24 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) followed by addition of lithium aluminum hydride (0.02 g,0.48 mmol) with ice water bath and the whole system stirred overnight at room temperature and TLC detection until no starting material remained. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=100:1-15:1) to give 53 (0.08 g,73% yield.) MS m/z (ESI): 462.24[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 54:
synthesis of intermediate A':
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 20mL of methylene chloride, followed by 4-toluenesulfonyl chloride (1.43 g,7.49 mmol), reacted at room temperature for 4 hours, TLC was monitored to completion, 20mL of water was added to the system, methylene chloride extraction (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (20 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the crude product was isolated and purified by column chromatography (petroleum ether: ethyl acetate=1:1) to give intermediate A' (1.07 g, 73%). MS m/z (ESI): 293.1[ M+1]
Synthesis of intermediate 1 a':
4-bromo-2-methylaminoaniline (2.00 g,9.94 mmol) was dissolved in 50mL tetrahydrofuran followed by carbonyldiimidazole (2.40 g,14.9 mmol) and the system stirred overnight at room temperature, followed by TLC monitoring until no starting material remained. The reaction was directly purified by column chromatography (dichloromethane: methanol=30:1) to give 1a' (0.76 g, 34% yield). MS m/z (ESI): 226.9[ M+1]
Synthesis of intermediate 1 b':
1a' (0.76 g,3.34 mmol) was dissolved in 15mL of N, N-dimethylformamide followed by addition of 2-chloroethyl dimethylamine (669 mg,6.68 mmol), potassium carbonate (924 mg,10.02 mmol) and sodium iodide (502 mg,3.34 mmol), and the whole system was stirred at 50℃for 8h, followed by TLC monitoring until no starting material remained. To the reaction solution was added 50mL of water, 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 then the solvent was removed under reduced pressure, and purified by column chromatography (ethyl acetate: methanol=30:1) to give 1b' (0.39 g, yield 39%). MS m/z (ESI): 298.0[ M+1]
Synthesis of intermediate 1 c':
1b '(160 mg,0.54 mmol) was dissolved in 15mL of 1, 4-dioxane, then 2-methoxy-3, 4-fluoro-phenylboronic acid (126 mg,0.80 mmol), tetrakis triphenylphosphine palladium (31 mg,0.03 mmol) and potassium phosphate trihydrate (215 mg,0.80 mmol) were added, the whole system was left under nitrogen atmosphere, the whole system was stirred at 100℃under room temperature for 4h, TLC monitoring was followed until no starting material remained, and the reaction was purified by direct column chromatography (dichloromethane: methanol=20:1) to give 1c' (174 m g, yield 90%). MS m/z (ESI): 362.1[ M+1]
Synthesis of intermediate 1 d':
1c' (74 mg,0.21 mmol) was dissolved in 5mL dichloromethane, followed by slow dropwise addition of boron tribromide (160 mg,0.63 mmol) under ice-bath, the whole system was stirred at room temperature, reacted for 4h, and TLC monitoring was followed until no starting material remained. To the reaction solution was added 20mL of water, 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, and separated and purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give 1d' (30 mg, yield 42%). MS m/z (ESI): 348.1[ M+1]
Synthesis of the final product (compound 1'):
1c (30 mg,0.086 mmol) was dissolved in 5mL of N, N-dimethylformamide followed by intermediate A' (30 mg,0.086 mmol) and potassium carbonate (24 mg,0.173 mmol) and the whole system stirred at 50℃and reacted for 4h with TLC monitoring and tracking until no starting material remained. To the reaction solution was added 30mL of water, 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, and the resultant was purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give the final product 1' (37 mg, yield 90%). MS m/z (ESI): 484.2[ M+1]
1 H NMR(600MHz,CDCl 3 )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,1H),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).
Example 55:
synthesis of intermediate 2 a':
1b' (160 mg,0.54 mmol) was dissolved in 15mL of 1, 4-dioxane, then 3-fluoro-2-hydroxyphenylboronic acid (126 mg,0.81 mmol), tetrakis triphenylphosphine palladium (31 mg,0.03 mmol) and potassium phosphate trihydrate (215 mg,0.81 mmol) were added, the whole system was left under nitrogen atmosphere, stirred at 100℃for 4h at room temperature, and TLC monitoring was followed until no starting material remained. The reaction was purified by direct column chromatography (dichloromethane: methanol=20:1) to give 2a' (157 mg, yield 89%). MS m/z (ESI): 330.2[ M+1]
Synthesis of the final product (compound 2'):
2a '(100 mg,0.30 mmol) was dissolved in 5mL of N, N-dimethylformamide, followed by addition of A' (64 mg,0.30 mmol) and potassium carbonate (63 mg,0.46 mmol), the whole was stirred at 50℃and reacted for 4h, followed by TLC monitoring until no starting material remained. To the reaction solution was added 30mL of water, 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, and separated and purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give the final product 2' (50 mg, yield 35%). MS m/z (ESI): 466.1[ M+1]
1 H NMR(600MHz,DMSO-d 6 )δ7.31(s,1H),δ7.25-7.22(m,1H)，δ7.20-7.15(m,4H),δ3.95-3.90(m,2H),δ3.63-3.60(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).
Example 56:
synthesis of intermediate 3 a':
5-bromo-2-benzoxazolone (1.70 g,8.0 mmol) was dissolved in 30mL of N, N-dimethylformamide, then dimethylaminochloroethane hydrochloride (1.40 g,9.6 mmol) and potassium carbonate (3.30 g,2.4 mmol) were added while ice-bath, and the reaction was stirred at 125℃for 4h. After completion of the reaction, 100mL of water was added to the reaction mixture, extraction was performed 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, and separated and purified by column chromatography (dichloromethane: methanol=50:1 to 15:1) to give 3a' (1.70 g, yield 64%). MS m/z (ESI): 285.0[ M+1]
Synthesis of intermediate 3 b':
3a' (600 mg,2.1 mmol) was dissolved in 20mL dioxane and 4mL water, then the compound 3, 4-difluoro-2-methoxyphenylboronic acid (595 mg,3.15 mmol) and palladium tetraphenylphosphine (122 mg,0.11 mmol) and potassium phosphate trihydrate (838 mg,3.15 mmol) were added and the reaction stirred at 100℃for 4h. After the completion of the reaction, 30mL of water was added to the reaction mixture, extraction was performed 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, and separated and purified by column chromatography (dichloromethane: methanol=50:1 to 15:1) to give 3b' (250 mg, yield 34%). MS m/z (ESI): 349.1[ M+1]
Synthesis of intermediate 3 c':
3b' (250 mg,0.72 mmol) was dissolved in 20mL of dichloromethane and then boron tribromide (375 mg,1.44 mmol) was slowly added dropwise under an ice-water bath and stirred overnight at room temperature. After the completion of the reaction, 30mL of water was added to the reaction mixture, extraction was performed 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, and separated and purified by column chromatography (dichloromethane: methanol=50:1 to 10:1) to give 3c' (200 mg, yield 83%). MS m/z (ESI): 335.1[ M+1]
Synthesis of the final product (compound 3'):
3c '(200 mg,0.60 mmol) was dissolved in 15mL of N, N-dimethylformamide, then intermediate A' (184 mg,0.60 mmol) and potassium carbonate (165 mg,1.2 mmol) were added and the reaction stirred at 50℃for 3h. After the completion of the reaction, 30mL of water was added to the reaction mixture, extraction was performed 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, and separated and purified by column chromatography (dichloromethane: methanol=50:1 to 10:1) to give 3' (135 mg, yield 48%). MS m/z (ESI): 471.2[ M+1]
1 HNMR(600MHz，CDCl 3 )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).
Example 57:
synthesis of intermediate 4 a':
3a' (600 mg,2.10 mmol) was dissolved in 20mL dioxane and 4mL water, then 3-fluoro-2-hydroxyphenylboronic acid (494 mg,3.15 mmol) and palladium tetraphenylphosphine (122 mg,0.11 mmol) and potassium phosphate trihydrate (843 mg,3.15 mmol) were added and the reaction stirred at 100℃for 4h. After the completion of the reaction, 50mL of water was added to the reaction mixture, extraction was performed 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, followed by separation and purification by column chromatography (dichloromethane: methanol=50:1 to 15:1) to give 4a' (400 mg, yield 60%). MS m/z (ESI): 317.1[ M+1]
Synthesis of the final product (compound 4'):
4a '(150 mg,0.47 mmol) was dissolved in 10mL of N, N-dimethylformamide, 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℃for 3h. After the completion of the reaction, 30mL of water was added to the reaction mixture, extraction was performed 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, and separated and purified by column chromatography (dichloromethane: methanol=50:1 to 10:1) to give 4' (145 mg, yield 68%). MS m/z (ESI): 453.2[ M+1]
1 HNMR(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).
Example 58:
synthesis of intermediate 5 a':
1b' (160 mg,0.54 mmol) was dissolved in 15mL of 1, 4-dioxane, followed by 4-fluoro-2-hydroxyphenylboronic acid (126 mg,0.81 mmol), tetrakis triphenylphosphine palladium (31 mg,0.03 mmol) and potassium phosphate trihydrate (215 mg,0.81 mmol) were added, the whole system was replaced three times with nitrogen, the reaction was stirred at 100℃for 4h under nitrogen, and TLC monitoring was followed until no starting material remained. The reaction was purified by direct column chromatography (dichloromethane: methanol=20:1) to give 5a' (157 m g, 89% yield). MS m/z (ESI): 330.2[ M+1]
Synthesis of the final product (compound 5'):
5a '(100 mg,0.30 mmol) was dissolved in 10mL of N, N-dimethylformamide, followed by intermediate A' (64 mg,0.30 mmol) and potassium carbonate (63 mg,0.46 mmol) were added and the reaction stirred at 50℃for 4h, followed by TLC monitoring until no starting material remained. To the reaction solution was added 30mL of water, 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, and separated and purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give the final product 5' (72 mg, yield 51%). MS m/z (ESI): 466.1[ M+1]
1 H NMR(600MHz，CDCl 3 )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).
Example 59:
synthesis of intermediate 6 a':
2-fluoro-4-bromonitrobenzene (5.00 g,22.7 mmol) was dissolved in 50mL 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 under nitrogen protection for 12h. TLC monitoring showed the reaction was complete. 200mL 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 give intermediate 6a' (5.03 g, 96% yield). MS m/z (ESI): 231.1[ M+1]
Synthesis of intermediate 6 b':
intermediate 6a' (5.03 g,21.7 mmol) was dissolved in absolute 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 portions. The system was reacted at 70℃for 4 hours, during which time the system color changed from yellow to colorless. TLC monitoring showed the reaction was complete. After the system was filtered, the filtrate was concentrated to remove the organic solvent. The aqueous phase was extracted with ethyl acetate (50 mL. Times.3). The combined organic phases were washed with saturated sodium chloride (30 mL. Times.2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to give intermediate 6b' (4.70 g, crude). The product was used directly in the next reaction without further purification. MS m/z (ESI) 201.1[ M+1]
Synthesis of intermediate 6 c':
intermediate 6b' (2.00 g,9.9 mmol) was dissolved in 20mL of dichloromethane and carbonyldiimidazole (1.77 g,10.9 mmol) was added in one portion and reacted at room temperature under nitrogen for 1h. The system turned brown. Liquid monitoring showed complete consumption of raw materials. The system was filtered, the solid collected and dried in vacuo to afford intermediate 6c' (1.50 g, 66% yield). The product was used directly in the next reaction without further purification. MS m/z (ESI): 227.1[ M+1]
Synthesis of intermediate 6 d':
intermediate 6c' (1.50 g,6.6 mmol) was dissolved in 20mL of N, N-dimethylformamide, sodium hydride (792 mg,19.8mmol, 60%) was added at 0deg.C, and after stirring the system for 10 minutes dimethylaminochloroethane hydrochloride (1.50 g,9.9 mmol) was added. After that, the reaction was carried out at room temperature for 5 hours. TLC monitoring showed complete reaction with target mass spectrum formation. 70mL of water was added to the reaction mixture, and the mixture was stirred for 3 minutes, followed by extraction with ethyl acetate (30 mL. Times.3). The organic phases were combined, washed with saturated sodium chloride (20 ml x 2) and the organic phase was 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), and the product fractions were collected, combined and concentrated to give intermediate 6d' (1.10 g, yield 56%). MS m/z (ESI): 298.2[ M+1]
Synthesis of intermediate 6 e':
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 is reacted for 10 hours at 100 ℃ under the protection of nitrogen. The liquid showed complete reaction. 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 isolated and purified by thin plate chromatography (ethyl acetate: methanol=5:1) to give intermediate 6e' (60 mg, 18% yield). MS m/z (ESI): 330.1[ M+1]
Synthesis of the final product (compound 6'):
intermediate 6e' (0.06 g,0.18 mmol) and 2- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) ethanol (28 mg,0.18 mmol) were dissolved in 5mL tetrahydrofuran, tributylphosphine (73.71 mg,0.36 mmol) and azodicarbonyl dipiperidine (92 mg,0.36 mmol) were added at 0deg.C. The system was reacted at room temperature under nitrogen protection for 12h. Liquid monitoring showed complete reaction. After the system was filtered, the filtrate was concentrated. Column chromatography separation and purification (dichloromethane: methanol=40:1-20:1) gave the final product 6' (41 mg, 46% yield). MS m/z (ESI): 466.2[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 60:
synthesis of intermediate 7 a':
intermediate 6d '(0.30 g,1.0 mmol) and 3-chloro-2-hydroxyphenylboronic acid (260 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 is reacted for 10 hours at 100 ℃ under the protection of nitrogen. The liquid showed complete reaction. 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 isolated by thin plate chromatography (ethyl acetate: methanol=5:1) to afford intermediate 7a' (0.20 g, 58% yield). MS m/z (ESI): 345.8[ M+1]
Synthesis of the final product (compound 7'):
intermediate 7a' (0.03 g,0.087 mmol) and 2- (1, 3, 5-trimethyl-1H-pyrazol-4-yl) ethanol (26 mg,0.17 mmol) were dissolved in 5mL tetrahydrofuran and triphenylphosphine (45 mg,0.17 mmol) and diisopropyl azodicarboxylate (35 mg,0.17 mmol) were added at 0deg.C. The system was reacted at room temperature under nitrogen protection for 12h. Liquid monitoring showed complete reaction. After the system was filtered, the filtrate was concentrated. Column chromatography separation and purification (dichloromethane: methanol=40:1-20:1) gave the final product 7' (21 mg, 47% yield). MS m/z (ESI): 482.0[ M+1]
1 H NMR(600MHz,CDCl 3 )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).
Example 61:
synthesis of intermediate 8 a':
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), triphenylphosphine (27.5 g,104.7 mmol) were dissolved in 70mL of tetrahydrofuran, and diisopropyl azodicarboxylate (21.2 g,104.7 mmol) was added at 0deg.C under nitrogen. The system was allowed to react at room temperature for 12h and tlc monitoring indicated complete reaction. To the reaction solution was added 50mL of water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The crude product was isolated by column chromatography (petroleum ether: ethyl acetate=10:1) to give intermediate 8a' (12.0 g, 70% yield).
MS m/z(ESI):327.2[M+1]
Synthesis of intermediate 8 b':
intermediate 8a '(2.00 g,6.1 mmol) and bippinacol borate (4.66 g,18.3 mmol) were dissolved in 30mL 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 is reacted for 12 hours at 100 ℃ under the protection of nitrogen. TLC monitoring showed the reaction was complete. 50mL of water was added to the system, extracted with dichloromethane (30 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude product which was separated by column chromatography (petroleum ether: ethyl acetate=10:1) to give intermediate 8b' (2.00 g, yield 61%). MS m/z (ESI): 375.2[ M+1]
Synthesis of intermediate 8 c':
2-fluoro-4-bromonitrobenzene (2.00 g,9.1 mmol) was dissolved in 40mL of N, N-dimethylformamide, followed by N, N-dimethylethylenediamine (1.00 g,11.3 mmol) and triethylamine (1.40 g,13.6 mmol), and the whole was stirred at room temperature for 2.5h and no starting material remained by TLC. To the reaction solution was added 100mL of water, extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), and dried over anhydrous sodium sulfate to give 8c' (2.50 g, yield 96%). MS m/z (ESI): 288.0[ M+1]
Synthesis of intermediate 8 d':
8c' (2.50 g,8.7 mmol) was dissolved in 60mL of ethanol-water mixture (ethanol: water=5:1), followed by iron powder (1.26 g,22.5 mmol) and 6mL of saturated ammonium chloride solution, and the whole system was refluxed at 80℃and examined by TLC until no starting material remained. The reaction system was cooled to room temperature and then filtered through celite. The celite was rinsed with 50mL of ethyl acetate, all the filtrate was collected and the solvent was removed under reduced pressure to give crude product. After separation and purification of the crude product by column chromatography (dichloromethane: methanol=20:1-10:1), 8d' (2.00 g, 89% yield) was obtained. MS m/z (ESI): 258.0[ M+1]
Synthesis of intermediate 8 e':
intermediate 8d' (20.0 g,77.5 mmol) was dissolved in 210mL of dichloromethane and carbonyldiimidazole (13.8 g,85.2 mmol) was added. The system was reacted at room temperature for 12h. TLC monitoring showed the reaction was complete. 100mL of water was added to the system, extracted with methylene chloride (100 mL. Times.3), and the organic phases were combined, washed with saturated brine, and concentrated. The crude product was slurried with methyl tert-butyl ether (50 mL), filtered and dried to give intermediate 8e' (15.0 g, 68% yield). MS m/z (ESI): 284.2[ M+1]
Synthesis of the final product (compound 8'):
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 is reacted for 12 hours at 100 ℃ under the protection of nitrogen. The liquid showed complete reaction. The system was concentrated by filtration and purified by column chromatography (dichloromethane: methanol=20:1-15:1) to give the final product 8' (0.80 g, yield 50%). MS m/z (ESI): 452.2[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 62:
synthesis of intermediate 9 a':
N-Boc-4-hydroxy piperidine (0.30 g,1.49 mmol) was dissolved in 5mL dichloromethane followed by triethylamine (226.3 mg,2.24 mmol) followed by methylsulfonyl chloride (205 mg,1.79 mmol) slowly in an ice bath and the system was reacted at room temperature for 2h and TLC monitoring was followed until no starting material remained. To the reaction solution was added 10mL of water, extracted with dichloromethane (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 to give intermediate 9a' (416 mg, yield 100%). MS m/z (ESI) 280.1[ M+1]
Synthesis of intermediate 9 b':
compound 8 (0.10 g,0.22 mmol) was dissolved in 2mL of N, N-dimethylformamide, sodium hydrogen (18 mg,0.44mmol,60% content) was slowly added under ice-bath, stirred for 5mins, then intermediate 9a' was added to the reaction solution, stirred at room temperature for 2h, and TLC monitoring was followed until no starting material remained. 10mL of saturated aqueous ammonium chloride was added to the system, extracted with dichloromethane (5 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (5 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 9b' (0.30 g, crude product) which was directly used in the next reaction.
Synthesis of the final product (compound 9'):
intermediate 9b' (0.30 g, crude) was dissolved in 5mL dichloromethane, followed by 1mL trifluoroacetic acid, and the system was reacted at room temperature for 12h, followed by tlc monitoring until no starting material remained. The solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give the final product 9' (20 mg, 17% yield in 2 steps). MS m/z (ESI): 535.3[ M+1]
1 H NMR(600MHz,CDCl 3 )δ7.60-7.56(m,1H),7.30(d,J＝8.4Hz,1H),7.24(d,J＝1.6Hz,1H),7.21-7.10(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).
Example 63:
synthesis of intermediate 10 a':
5-bromo-1, 3-dihydrobenzimidazol-2-one (1.00 g,4.7 mmol) was dissolved in 10mL of N, N-dimethylformamide, sodium hydride (1.50 g,37.6mmol,60% content) and 2-chloroethyl dimethylamine hydrochloride (2.70 g,18.8 mmol) were slowly added under ice-bath, the reaction was stirred at room temperature for 10h and monitored by TLC until no starting material remained. To the system was added 30mL of saturated aqueous ammonium chloride, extracted with dichloromethane (15 ml×3), the organic phases were combined, washed with saturated sodium chloride (15 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=40:1) to give intermediate 10a' (0.50 g, yield 22%). MS m/z (ESI): 355.1[ M+1]
Synthesis of the final product (compound 10'):
a solution of intermediate 10a ' (0.15 g,0.42 mmol) in 5mL tetrahydrofuran and 0.5mL water was added, followed by intermediate 8b ' (316 mg,0.84 mmol), potassium carbonate (117 mg,0.84 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (31 mg,0.042 mmol), the whole was replaced with nitrogen three times, the reaction was stirred at 100℃for 10h under nitrogen atmosphere, and TLC monitoring was followed until no starting material remained. The solvent was removed under reduced pressure and purified by direct column chromatography (dichloromethane: methanol=20:1) to give the final product 10' (37 mg, 16% yield). MS m/z (ESI): 523.3[ M+1]
1 H NMR(600MHz,DMSO-d 6 )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).
Example 64:
synthesis of intermediate 11 a':
n-hydroxyethyl piperidine (0.30 g,2.3 mmol) was dissolved in 5mL dichloromethane followed by triethylamine (352 mg,3.5 mmol) followed by methylsulfonyl chloride (319 mg,2.8 mmol) slowly in an ice bath and the system was reacted at room temperature for 2h with TLC monitoring tracking until no starting material remained. The solvent was removed under reduced pressure to give intermediate 11a' (481 mg, yield 100%) which was used directly in the next reaction. MS m/z (ESI): 208.0[ M+1]
Synthesis of the final product (compound 11'):
compound 8 '(0.08 g,0.17 mmol) was dissolved in 2mL of N, N-dimethylformamide, sodium hydride (14 mg,0.35mmol,60% content) was slowly added under ice-bath, stirred for 5mins, then intermediate 11a' was added to the reaction solution, stirred at room temperature for 2h, and TLC monitoring was followed until no starting material remained. 10mL of saturated aqueous ammonium chloride was added to the system, extracted with dichloromethane (5 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (5 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=40:1-20:1) to give the final product 11' (28 mg, yield 27%). MS m/z (ESI): 563.3[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 65:
synthesis of intermediate 12 a':
Bis (trichloromethyl) carbonate (3.45 g,11.6 mmol) was dissolved in 70mL of methylene chloride, and a methylene chloride solution (30 mL) of m-bromoaniline and triethylamine was then slowly added dropwise under nitrogen atmosphere and ice bath, and the reaction was carried out at room temperature for 0.5h. The above liquid was then slowly added dropwise to 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 and ice bath, the system was reacted at room temperature for 3h and TLC monitoring was followed until no starting material remained. 200mL of water was added to the reaction mixture, extraction was performed with ethyl acetate (100 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, petroleum ether: ethyl acetate (30 ml:10 ml) was recrystallized to give intermediate 12a' (2.70 g, 38% yield). MS m/z (ESI): 244.9[ M+1]
Synthesis of intermediate 12 b':
intermediate 12a' was dissolved in 50mL of dichloromethane, and [ bis (trifluoroacetoxy) iodo ] benzene (5.70 g,13.3 mmol) was added at-10 ℃ and the system reacted at this temperature for 0.5h with tlc monitoring tracking until no starting material remained. To the reaction solution was added 50mL of water, 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, followed by column chromatography separation and purification (petroleum ether: ethyl acetate=20:1-1:1) to give intermediate 12b' (0.65 g, yield 26%). MS m/z (ESI): 242.9[ M+1]
Synthesis of intermediate 12 c':
intermediate 12b' (0.60 g,2.5 mmol) was dissolved in 10mL of N, N-dimethylformamide, sodium hydrogen (350 mg,60% content) was slowly added at 0deg.C, the system was reacted at room temperature for 10h, then 2-chloroethyl dimethylamine (711 mg,5.0 mmol) was added to the reaction solution, the system was reacted at room temperature for 3h, and TLC monitoring was followed until no starting material remained. To the reaction solution was added 30mL of water, extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (15 mL. Times.2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give intermediate 12c' (0.80 g), which was directly taken as the next step. MS m/z (ESI) 314.0[ M+1]
Synthesis of the final product (compound 12'):
a solution of intermediate 12c ' (0.60 g,1.9 mmol) in 15mL of tetrahydrofuran and 1.5mL of water was added, followed by 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), and the whole was replaced with nitrogen three times, and the reaction was stirred at 100℃for 10 hours under nitrogen atmosphere, followed by TLC monitoring until no starting material remained. The solvent was removed under reduced pressure and purified by direct column chromatography (dichloromethane: methanol=20:1) to give the final product 12' (80 mg, yield 18%). MS m/z (ESI): 482.2[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 66:
synthesis of the final product (compound 13'):
compound 8' (0.10 g,0.22 mmol) was dissolved in 5mL of dichloromethane, triethylamine (47 mg,0.46 mmol) was then added, acetyl chloride (35 mg,0.44 mmol) was then added and the reaction stirred at room temperature for 12h, and TLC monitored no starting material remained. 10mL of water was added to the reaction mixture, extraction was performed with methylene chloride (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (30 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was separated and purified by column chromatography (methylene chloride: methanol=40:1-20:1) to give a final product 13' (10 mg, yield 17%) MS m/z (ESI): 494.2[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 67:
synthesis of the final product (compound 14'):
compound 8' (100 mg,0.22 mmol) was dissolved in 5mL of dichloromethane, followed by 3-thiopheneboronic acid (57 mg,0.44 mmol), triethylamine (112 mg,1.1 mmol), 4A MS (150 mg) and copper acetate (80 mg,0.44 mmol) were added, the whole system was left under an atmosphere of oxygen three times and reacted at room temperature for 10h, followed by TLC monitoring until no starting material remained. The solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=30:1-20:1) to give final product 14' (85 mg, yield 71%). MS m/z (ESI): 536.2[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 68:
synthesis of intermediate 15 a':
intermediate 7a' (5.90 g,25.5 mmol) was dissolved in 100mL tetrahydrofuran followed by 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 3h reaction at 15 ℃, the temperature is raised to 60 ℃ for 10h reaction. TLC monitored reaction was complete. N, N' -dimethylethylenediamine (15.0 g) was added to the reaction solution, and the reaction was stirred for 0.5 hours. 50mL of saturated aqueous citric acid solution was added thereto, and the reaction was stirred for 0.5h. The aqueous phase (30 mL. Times.2) was extracted with ethyl acetate, the organic phase was collected, washed with saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated to afford intermediate 15a' (8.70 g, crude). The reaction mixture was used in the next reaction without purification. MS m/z (ESI): 331.0[ M+1]
Synthesis of intermediate 15 b':
intermediate 15a' (6.70 g,20.2 mmol) was dissolved in 100mL of ethanol and 40mL 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℃for 10h. TLC monitored reaction was complete. The organic phase was filtered and concentrated, followed by 50mL of water, extraction with ethyl acetate (50 mL x 2), washing with saturated aqueous sodium chloride (30 mL), drying over anhydrous sodium sulfate, filtration and concentration of the organic phase afforded intermediate 15b' (3.20 g, 53% yield). The reaction mixture was used in the next reaction without purification. MS m/z (ESI): 301.0[ M+1]
Synthesis of intermediate 15 c':
intermediate 15b' (2.00 g,6.6 mmol) was dissolved in 20mL1, 2-dichloroethane followed by chloroacetaldehyde (3.91 g,19.9 mmol). The system was reacted at 10℃for 0.5h. Sodium triacetoxyborohydride (9.85 g,46.5 mmol) was added thereto and reacted at 10℃for 10 hours. TLC monitored reaction was complete. The reaction was quenched by addition of 50mL of water, adjusted to PH 7-8 using saturated aqueous sodium bicarbonate, extracted with dichloromethane (50 ml×2), the organic phase was collected, washed with saturated aqueous sodium chloride (30 ml×2), dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated and purified by column chromatography (petroleum ether: ethyl acetate=4:1) to give intermediate 15c' (1.00 g, 41% yield). MS m/z (ESI): 365.0[ M+1]
Synthesis of intermediate 15 d':
intermediate 15c' (1.00 g,2.7 mmol) was dissolved in 5mL 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℃for 10h. TLC monitored reaction was complete. 50mL of water was added to the system, dichloromethane extraction (30 mL. Times.2), washing of the organic phase with saturated aqueous sodium chloride (30 mL. Times.2), drying over anhydrous sodium sulfate, filtration and concentration of the organic phase, and separation and purification by column chromatography (petroleum ether: ethyl acetate: methanol: methylamine=1:1:0:0.01-0:3:1:0.01) gave intermediate 15d' (0.50 g, yield 49%). MS m/z (ESI): 372.1[ M+1]
Synthesis of intermediate 15 e':
intermediate 15d' (0.50 g,1.4 mmol) was dissolved in 2mL ethyl acetate and then 4M ethyl acetate hydrochloride solution (20 mL) was added and the system reacted at room temperature for 2h. The liquid monitoring reaction is complete. The organic solvent was concentrated, the residue was dissolved in 15mL of acetonitrile, potassium carbonate (0.30 g) was added, the organic phase was filtered and concentrated to give intermediate 15e' (0.40 g, crude). The reaction mixture was used in the next reaction without purification. MS m/z (ESI): 272.0[ M+1]
Synthesis of intermediate 15 f':
intermediate 15e '(0.20 g,0.73 mmol) was dissolved in 5mL of 1, 2-dichloroethane followed by the addition of N, N' -thiocarbonyldiimidazole (1.31 g,7.4 mmol). The system was reacted at 80℃for 15h. TLC monitored reaction was complete. To the system was added 20mL of water, extracted with dichloromethane (20 ml×2), the organic phase was collected, washed with saturated aqueous sodium chloride (20 ml×2), dried over anhydrous sodium sulfate, filtered and the organic phase was concentrated, and the separated and purified by column chromatography (petroleum ether: ethyl acetate=30:1-0:1) to give intermediate 15f' (0.25 g, yield 72%). MS m/z (ESI) 316.0[ M+1]
Synthesis of the final product (compound 15'):
intermediate 15f ' (0.20 g,0.64 mmol) and intermediate 8b ' (470 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 nitrogen was purged three times. The system was reacted at 100℃for 4h. The liquid monitoring reaction is complete. The organic phase was filtered and concentrated and purified by column chromatography (dichloromethane: methanol=30:1-20:1) to give the final product 15' (44 mg, 14% yield). MS m/z (ESI): 482.2[ M+1]
1 H NMR(600MHz,DMSO-d 6 ) Delta 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:
synthesis of intermediate 16 a':
6-bromo-1-methyl-1, 3-dihydro-2H-benzimidazol-2-one (0.25 g,1.1 mmol) was dissolved in 3mL of N, N-dimethylformamide and sodium hydride (0.17 g,4.4mmol, 60%) was added at 0deg.C. After stirring the system for 10 min, N-dimethyl-2-chloroethylamine hydrochloride (0.31 g,2.2 mmol) was added and the system was reacted at room temperature for 10h, and TLC monitoring showed the reaction was complete. Aqueous ammonium chloride was quenched (2 mL), concentrated, added water (20 mL) and dichloromethane (20 mL), and separated. The aqueous phase was extracted with dichloromethane (20 ml×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give intermediate 16a' (0.30 g, 73% yield). The reaction mixture was used in the next reaction without purification. MS m/z (ESI): 298.2[ M+1]
Synthesis of the final product (compound 16'):
intermediate 16a ' (0.15 g,0.5 mmol) and intermediate 8b ' (376mg, 1.01 mmol) were dissolved in dioxane (5 mL) and water (1 mL), and potassium carbonate (208 mg,1.5 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (29 mg,0.04 mmol) were added. The system was reacted at 100℃under nitrogen for 12h. The liquid showed complete reaction. Cooling, filtering, and concentrating the filtrate. Purification by column chromatography (dichloromethane: methanol=30:1-20:1) afforded the final product 16' (63 mg, 24% yield). MS m/z (ESI): 466.3[ M+1]
1 H NMR(600MHz,CD 3 OD)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).
Example 70:
synthesis of intermediate 17 a':
potassium fluoride (438 mg,7.6 mmol) was dissolved in 5mL of water, followed by addition of aluminum trichloride (865 mg,8.5 mmol), and the system was reacted at 10℃for 1h, followed by removal of water under reduced pressure to give a crude product. The crude product and 6-bromo-2, 3-dihydro-1H-indole (0.40 g,1.9 mmol) were dissolved in 15mL acetonitrile and 2-chloroethyl dimethylamine hydrochloride (326 mg,2.2 mmol) was added and reacted at 80℃for 3H, followed by TLC monitoring until no starting material remained. To the reaction solution was added 30mL of water, 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, and 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]
Synthesis of the final product (compound 17'):
a solution of intermediate 17a ' (150 mg,0.53 mmol) in 5mL of tetrahydrofuran and 0.5mL of water was added, followed by intermediate 8b ' (390 mg,1.1 mmol), potassium carbonate (146 mg,1.1 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (39 mg,0.53 mmol), and the whole was replaced with nitrogen three times, and the reaction was stirred at 100℃for 10h under nitrogen atmosphere, followed by TLC monitoring until no starting material remained. The solvent was removed under reduced pressure, and purified by direct column chromatography (dichloromethane: methanol=20:1) to give the final product 17' (26 mg, yield 10%). MS m/z (ESI): 482.2[ M+1]
1 H NMR(600MHz,DMSO-d 6 )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).
Test example 1 screening activity data for NMT inhibitor cell level
Screening purpose:
the compounds were tested for in vitro anti-Human Rhinovirus (HRV) activity using cytopathic effect (CPE) assays.
Screening system:
HeLa cells infected with HRV.
HRV subtype: HRV 1b; HRV 14.
The test method comprises the following steps:
compounds (3-fold serial dilutions, 8 concentration points, double multiplex wells) and virus were added to 384 well cell culture plates and incubated at 5% CO 2 Incubation was performed at 33℃for 1 hour. H1 HeLa cells were then seeded into the test plates at a density of 15,000 cells per well and at 5% CO 2 Culturing in 33 deg.C incubator for 2 days until no compound virus infects the cytopathy in control hole to 80-95%. The final DMSO concentration was 0.5%. The antiviral activity of a compound is represented by the inhibition (%) of the compound at different concentrations against the cytopathic effect caused by the virus. The calculation formula is as follows:
inhibition (%) = (test well read-virus control mean)/(cell control mean-virus control mean) ×100
Nonlinear fitting analysis of inhibition of compounds using GraphPad Prism software, the median effective concentration of compounds (EC 50 ) Values.
Compound screening results:
data on rhinovirus inhibitory Activity of the compounds of Table 1
Conclusion of the test: according to the data in the table, the compounds of the invention have a strong inhibition effect on human rhinoviruses (HRV 1B and HRV 14 subtypes).
Test example 2 in vitro inhibition of SU-DHL-2/MIA PaCa-2 cell proliferation by NMT inhibitors
1. Purpose of test
The in vitro inhibition of cell proliferation by the synthetic compounds was examined.
2. Principle of testing
MTT is a tetrazolium salt of a dye that accepts a hydrogen atom under the trade name thiazole blue. Amber dehydrogenase in mitochondria of living cells can reduce exogenous MTT to insoluble bluish violet crystals and deposit in cells, whereas dead cells do not. The dimethyl sulfoxide can dissolve blue-violet complex in cells, and the light absorption value of the blue-violet complex can be measured at the wavelength of 490-550nm by using an enzyme-linked immunosorbent assay, so that the number of the cells can be indirectly reflected. The amount of MTT crystals formed is proportional to the number of cells over a range of cell numbers. Diluting the medicine to be tested into different concentrations, adding into 96-well plate, after the medicine is acted for a certain time, measuring its OD value, and calculating its IC by using SPSS19.0 50 Values.
3. Test instrument
371 type CO2 incubator: thermo
IX70-142 inverted fluorescence microscope: olympus
HFsafe-1500 type biosafety cabinet: shanghai Lishen science instruments Co., ltd
Varloskan flash microplate reader: thermo Co Ltd
Precision electronic balance: mertrer AL204 type
4. Test materials:
4.1 cells and Medium
4.2 test materials
| Name of the name | Specification of specification | Manufacturing factories |
| Fetal bovine serum | 500 mL/bottle | Cellmo |
| PBS | 500 mL/bottle | Solarbio |
| DMSO | 500 mL/bottle | Light recovery |
| MTT | 5 g/bottle | Amresco |
4.3 preparation of reagents
5mg/mL MTT working solution: MTT 0.5g was weighed and dissolved in 100mL PBS, and the solution was sterilized by filtration through a 0.22 μm microporous filter membrane and stored in a refrigerator (for two weeks) at 4℃or for a long period of time at-20 ℃.
5. Test method
5.1 floor
Suspension cells: count after centrifugation. After preparing a cell suspension with a certain density by using a complete culture medium, uniformly inoculating the cell suspension into a 96-well plate by blowing, and then placing the cell suspension into 100 mu L of each well in CO 2 Culturing in an incubator.
5.2 pharmaceutical formulation
Weighing a proper amount of medicine, adding a calculated amount of DMSO for dissolution, subpackaging, and preserving at-20 ℃; preparation of 10mM concentration
5.3 dosing
Diluting the drug to several concentrations, adding into 96-well plate inoculated with cells, adding into CO 2 Culturing is continued in the incubator.
6. Detection of
The 96-well plate was removed and the cells were observed for cell fullness under a microscope. The MTT method is adopted for detection.
MTT method: MTT 20 mu L is added into each well, after the culture is carried out for about 4 hours in an incubator, liquid in the well is discarded, 150 mu L of DMSO is added into each well, the mixture is placed into a shaker for shaking for 5-10min, and the mixture is detected at a wavelength of 550nm by an enzyme-labeled instrument.
7. SPSS19.0 statistical software for data analysis, IC for calculating drugs 50 Values.
The compound screening results are shown in table 2:
table 2 compound cell proliferation inhibition assay data
Conclusion of experiment: according to the data in the table, the compounds of the invention have stronger inhibition effect on SU-DHL-2 and MIA CaPa-2 cells.
Test example 3 proliferation inhibition test of NMT inhibitor on other tumor cells
The cells and media used in this test example were as follows:
the test method of the test is the same as that of test example 2, and the measurement results are as follows:
table 3 data on inhibition of proliferation of several tumor cells by some of the compounds
Conclusion of experiment: according to the data in the table, the compound provided by the invention has a strong in vitro proliferation inhibition effect on various humanized tumor cells.
Claims (12)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
x is selected from- (CH) 2 ) r -wherein r is selected from 1,2,3,4 or 5;
y is absent or is
Wherein q is selected from 1,2,3 or 4;
R 1 independently selected from-F, -Cl, -Br, -CN, -OR 5 、-NR 5 R 6 、-NO 2 、-N 3 、-COOR 5 or-CONR 5 R 6 ，R 5 And R is 6 Each independently selected from H, C 1-6 An alkyl group;
n is 0,1,2 or 3;
a is heteroaryl;
R 4 independently selected from the group consisting of-F, -Cl-Br, -OH, -CN, -NO 2 、-N 3 、-SR 7 、-(CH 2 ) m C(O)R 7 、-(CH 2 ) m NR 7 R 8 、-(CH 2 ) m S(O)R 7 、-(CH 2 ) m S(O) 2 R 7 、-(CH 2 ) m OC(O)R 7 、-(CH 2 ) m C(O)OR 7 、-(CH 2 ) m OS(O) 2 R 7 、-(CH 2 ) m S(O) 2 OR 7 、-(CH 2 ) m C(O)NR 7 R 8 、-(CH 2 ) m S(O) 2 NR 7 R 8 、-(CH 2 ) m NR 7 C(O)R 8 、-(CH 2 ) m NR 7 S(O) 2 R 8 、-(CH 2 ) m NHC(＝NH)NR 7 R 8 、-(CH 2 ) 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 An alkoxy group;
m＝0，1，2，3，4；
s=0, 1,2,3,4,5 or 6;
R 7 and R is 8 Each independently selected from-H, -NH 2 -OH, 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 carbocyclyl, unsubstituted or s R 10 Substituted heterocyclyl;
or R is 7 And R is 8 Together with the nitrogen atom to which it is attached, form a 3-to 10-membered ring optionally having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 9 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
each R 10 Each independently selected from-F, -Cl,-Br、-OH、-CN、-NO 2 、-N 3 、SH、NH 2 (C.ident.CH), unsubstituted or s R 9 Substituted C 1-6 Alkyl, unsubstituted or s R 9 Substituted C 1-6 An alkoxy group;
p is 0,1,2,3 or 4;
w is selected from C, N or O; when W is O, R 3 Is absent;
R 2 and R is 3 Are each independently selected from-H, - (CH) 2 ) w C(O)R 11 、-(CH 2 ) w NR 11 R 12 、-(CH 2 ) w S(O)R 11 、-(CH 2 ) w S(O) 2 R 11 、-(CH 2 ) w OC(O)R 11 、-(CH 2 ) w C(O)OR 11 、-(CH 2 ) w OS(O) 2 R 11 、-(CH 2 ) w S(O) 2 OR 11 、-(CH 2 ) w NR 11 C(O)R 12 、-(CH 2 ) w NR 11 S(O) 2 R 12 、-(CH 2 ) w C(O)NR 11 R 12 、-(CH 2 ) w S(O) 2 NR 11 R 12 Unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 Alkoxy, - (CH) 2 ) w R 14 ；
w＝0，1，2，3，4；
t=0, 1,2,3,4,5 or 6;
R 11 and R is 12 Each independently selected from-H, -NH 2 -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 carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
or R is 11 And R is 12 Together with the nitrogen atoms to which they are attached form an optional moiety3-to 10-membered rings having 0-3 additional heteroatoms each independently selected from N, O or S;
each R 13 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH or C) 1-6 An alkoxy group;
R 14 selected from unsubstituted or t R 15 Substituted aryl, unsubstituted or t R 15 Substituted heteroaryl, unsubstituted or t R 15 Substituted carbocyclyl, unsubstituted or t R 15 Substituted heterocyclyl;
each R 15 Each independently selected from-F, -Cl, -Br, -OH, -CN, -NO 2 、-N 3 、SH、NH 2 (C.ident.CH), unsubstituted or t R 13 Substituted C 1-6 Alkyl, unsubstituted or t R 13 Substituted C 1-6 An alkoxy group;
z is selected from O or S;
unless otherwise indicated, aryl groups as described above contain 6 to 14 carbon atoms; carbocyclyl groups contain 3 to 10 carbon atoms and are non-aromatic; heteroaryl is a 5-to 10-membered heteroaryl; and the heterocyclic group is 3-10 membered heterocyclic group and is of a non-aromatic structure; heteroaryl or heterocyclyl contains one, two or more heteroatoms selected from N, O or S, the remainder being carbon atoms.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:
wherein A is a 5-6 membered heteroaryl group, the heteroaromatic ring contains 2-3 heteroatoms selected from N or O;
R 1 independently selected from-F or-Cl.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:
wherein A is selected from pyrazolyl or imidazolyl.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, characterized by having the structure of formula (II):
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 is-F;
R 16 independently selected from C 1-6 Alkyl, preferably methyl;
R 17 definition is as same as R 4 ；
u is 1 or 2.
5. The compound according to any one of claims 1 to 4, having a structure represented by formula (III):
6. a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, characterized by having the structure:
7. a pharmaceutical composition comprising a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
8. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an N-myristoyltransferase inhibitor.
9. The use according to claim 8, the medicament for the treatment or prevention of infectious diseases.
10. Use according to claim 9, characterized in that: the infectious diseases include protozoal infectious diseases or viral infectious diseases, preferably malaria and leishmaniasis, and the viral infectious diseases are human rhinovirus infectious diseases and HIV infectious diseases.
11. Use of a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, as an N-myristoyltransferase inhibitor for the manufacture of a medicament for the treatment or prophylaxis of hyperproliferative diseases.
12. The use according to claim 11, characterized in that: the hyperproliferative diseases are lymphoma, leukemia, pancreatic cancer, breast cancer, lung cancer, esophageal cancer, gastric cancer, liver cancer and colorectal cancer, and further the hyperproliferative diseases are B cell lymphoma.
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| CN101077866B (en) * | 2007-05-15 | 2012-07-11 | 中国人民解放军第二军医大学 | Substituted benzoxazoles antifungal compounds and preparation method thereof |
| GB0815947D0 (en) * | 2008-09-02 | 2008-10-08 | Univ Dundee | Compounds |
| US8048887B2 (en) * | 2008-09-11 | 2011-11-01 | Bristol-Myers Squibb Company | Compounds for the treatment of hepatitis C |
| GB201120993D0 (en) * | 2011-12-06 | 2012-01-18 | Imp Innovations Ltd | Novel compounds and their use in therapy |
| WO2016176449A1 (en) * | 2015-04-29 | 2016-11-03 | Janssen Pharmaceutica Nv | Benzimidazolone and benzothiazolone compounds and their use as ampa receptor modulators |
| GB201511382D0 (en) * | 2015-06-29 | 2015-08-12 | Imp Innovations Ltd | Novel compounds and their use in therapy |
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2020
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- 2020-07-14 CN CN202310199913.XA patent/CN116102541A/en active Pending
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| WO2021008512A1 (en) | 2021-01-21 |
| CN114174283B (en) | 2023-05-12 |
| CN114174283A (en) | 2022-03-11 |
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