CN112390760A - FAK-targeting compound and preparation method and application thereof - Google Patents

FAK-targeting compound and preparation method and application thereof Download PDF

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CN112390760A
CN112390760A CN202011105540.8A CN202011105540A CN112390760A CN 112390760 A CN112390760 A CN 112390760A CN 202011105540 A CN202011105540 A CN 202011105540A CN 112390760 A CN112390760 A CN 112390760A
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compound
fak
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CN112390760B (en
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张华北
齐月恒
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Beijing Normal University
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Abstract

The embodiment of the invention provides a compound targeting FAK, a preparation method and application thereof, wherein the compound has a structure shown in a general formula (I); the compound provided by the application has higher affinity with Focal Adhesion Kinase (FAK), and can be used as a compound targeting FAK; further, the FAK-targeting compounds of the present application have an inhibitory effect on focal adhesion kinase FAK and are therefore useful forPreparing a tumor treatment medicament; in addition, after the FAK-targeting compound provided by the application is subjected to radioactive chemical labeling, the FAK-targeting compound can be used as a tumor diagnosis imaging agent and used for preparing a tumor diagnosis medicament. The FAK-targeting compound has the characteristics of good affinity, strong specificity and high selectivity, and has clinical application value.
Figure DDA0002726826670000011

Description

FAK-targeting compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of compounds, in particular to a FAK-targeting compound and a preparation method and application thereof.
Background
Focal Adhesion Kinase (FAK) is an non-receptor tyrosine Kinase, which is highly or over-expressed in most tumor cells, plays an important role in various links such as tumor generation, development and metastasis, and especially plays an important role in the process of tumor evolution to a malignant invasive phenotype. In theory, the aim of inhibiting the invasion and metastasis of tumor cells can be achieved by blocking the expression of FAK or inhibiting the action of FAK. Therefore, FAK is a potential tumor diagnosis and treatment target.
The development of radiopharmaceuticals with high specificity and high sensitivity to tumors is essential. Over the past three decades, a number of radiopharmaceuticals have been designed and developed to image and identify the unique biochemical properties of tumor tissue. The high expression phenomenon of FAK in tumors can also be used for early diagnosis, treatment and prognosis evaluation of tumors on the radiopharmaceutical level.
Some FAK small-molecule inhibitors are already in clinical research on the aspect of common medicines in the prior art, but the tumor inhibition activity of the FAK small-molecule inhibitors is still to be improved. Therefore, there is a need to develop new FAK-targeting compounds, which can be directly used as tumor growth inhibitors on one hand, and can be used as FAK-targeting tumor early diagnosis agents after being labeled with radioisotopes on the other hand.
Disclosure of Invention
The application aims to provide a FAK-targeting compound and a preparation method and application thereof. The method specifically comprises the following steps:
in a first aspect, the present application provides a FAK targeting compound having the structure shown in formula (i):
Figure BDA0002726826650000021
wherein R is selected from
Figure BDA0002726826650000022
Figure BDA0002726826650000023
R1Is selected from-NO2、
Figure BDA0002726826650000024
Figure BDA0002726826650000025
R2Selected from-OH,
Figure BDA0002726826650000031
Figure BDA0002726826650000032
A second aspect of the present application provides a process for the preparation of a compound provided in the first aspect of the present application, comprising:
1) reacting a compound of formula (ii):
Figure BDA0002726826650000033
with a compound of general formula (III):
R’-NH2(Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure BDA0002726826650000034
wherein R' is selected from
Figure BDA0002726826650000041
Figure BDA0002726826650000042
R’1Is selected from-NO2、、
Figure BDA0002726826650000043
Figure BDA0002726826650000044
3) To be provided with
Figure BDA0002726826650000045
Substituted compounds
Figure BDA0002726826650000046
To obtain a compound of formula (V) or formula (VI):
Figure BDA0002726826650000051
4) to be provided with
Figure BDA0002726826650000052
Substituted compounds
Figure BDA0002726826650000053
Figure BDA0002726826650000054
Of (5) NO2Obtaining a compound of general formula (VII):
Figure BDA0002726826650000055
wherein R'2Selected from-OH,
Figure BDA0002726826650000061
5) reacting-NO in the compounds of the general formulae (IV) - (VII)2At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure BDA0002726826650000062
wherein R is as defined in claim 1;
when R is
Figure BDA0002726826650000063
When the compound is not substituted by fluorine-containing compounds;
when R is1Is composed of
Figure BDA0002726826650000064
The method also comprises the following reactions:
Figure BDA0002726826650000065
when R is2Is composed of
Figure BDA0002726826650000066
The method also comprises the following reactions:
Figure BDA0002726826650000071
a third aspect of the present application provides a precursor compound for the preparation of a compound as provided in the first aspect of the present application, selected from the following compounds:
Figure BDA0002726826650000072
Figure BDA0002726826650000081
the application also provides the application of the compound of the first aspect in the preparation of tumor treatment drugs and/or tumor diagnosis imaging agents, and a pharmaceutical composition containing the compound provided by the first aspect.
The compound provided by the application has higher affinity with Focal Adhesion Kinase (FAK), and can be used as a compound targeting FAK; furthermore, the FAK-targeting compound has an inhibition effect on focal adhesion kinase FAK, so that the FAK-targeting compound can be used for preparing tumor treatment medicines; in addition, after the FAK-targeting compound provided by the application is subjected to radioactive chemical labeling, the FAK-targeting compound can be used as a tumor diagnosis imaging agent and used for preparing a tumor diagnosis medicament. The FAK-targeting compound has the characteristics of good affinity, strong specificity and high selectivity, and has clinical application value.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is F-18 radioligand [ alpha ], [ beta ] -cyclodextrin18F]HPLC co-injection analysis chromatogram of 75 with its F-19 standard compound 75.
FIG. 2 is F-18 radioligand [ alpha ], [ beta ] -a18F]An HPLC co-injection analysis chromatogram of 83 with its F-19 standard compound 83.
FIG. 3 is F-18 radioligand [ alpha ], [ beta ] -cyclodextrin18F]HPLC co-injection analysis chromatogram of 84 with its F-19 standard compound 84.
FIG. 4 is F-18 radioligand [ 2 ]18F]102 and its F-19 standard compound 102.
FIG. 5 is F-18 radioligand [ 2 ]18F]103 and its F-19 standard compound 103.
FIG. 6 is the compound [ 2 ] in a mouse body18F]75, and the result is a distribution.
FIG. 7 is the compound [ 2 ]18F]75, uptake blocking assay results.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Abbreviations
THF tetrahydrofuran
DMF N, N-dimethylformamide
HATU 2-N, N, N ', N' -tetramethyluronium hexafluorophosphate
DIPEA N, N-diisopropylethylamine
FETos 2-fluoroethyl tosylate
-OTs p-toluenesulfonyloxy
In a first aspect, the present application provides a FAK targeting compound having the structure shown in formula (i):
Figure BDA0002726826650000101
wherein R is selected from
Figure BDA0002726826650000102
Figure BDA0002726826650000103
R1Is selected from-NO2、、
Figure BDA0002726826650000111
Figure BDA0002726826650000112
R2Selected from-OH,
Figure BDA0002726826650000113
In some preferred embodiments of the present application, the FAK-targeting compound has a structure represented by general formula (i):
Figure BDA0002726826650000114
wherein R is selected from
Figure BDA0002726826650000115
Figure BDA0002726826650000121
Wherein,
when R is2When it is-OH, R1Is selected from-NO2、
Figure BDA0002726826650000122
Figure BDA0002726826650000123
When R is2Is composed of
Figure BDA0002726826650000124
When R is1Is selected from-NO2、
Figure BDA0002726826650000125
Figure BDA0002726826650000126
When R is2Is selected from
Figure BDA0002726826650000127
When the current is over; r1is-NO2；
When R is2Is composed of
Figure BDA0002726826650000131
When R is1Is selected from
Figure BDA0002726826650000132
In particular, in some embodiments of the first aspect of the present application, the FAK-targeting compound is selected from the group consisting of:
Figure BDA0002726826650000133
Figure BDA0002726826650000141
Figure BDA0002726826650000151
in certain embodiments of the first aspect of the present application, when fluorine is present in the compound, at least one of the fluorine is substituted with a fluorine18And F is substituted.
In some embodiments of the first aspect of the present application, at least one fluorine is substituted with a fluorine atom18The F-substituted compound is selected from the following compounds:
Figure BDA0002726826650000161
Figure BDA0002726826650000171
a second aspect of the present application provides a process for the preparation of a compound as described in the first aspect of the present application, which comprises:
1) reacting a compound of formula (ii):
Figure BDA0002726826650000181
with a compound of general formula (III):
R’-NH2(Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure BDA0002726826650000182
wherein R' is selected from
Figure BDA0002726826650000183
Figure BDA0002726826650000184
R’1Is selected from-NO2、
Figure BDA0002726826650000191
Figure BDA0002726826650000192
3) To be provided with
Figure BDA0002726826650000193
Substituted compounds
Figure BDA0002726826650000194
To obtain a compound of formula (V) or formula (VI):
Figure BDA0002726826650000195
4) to be provided with
Figure BDA0002726826650000196
Substituted compounds
Figure BDA0002726826650000197
Figure BDA0002726826650000201
Of (5) NO2Obtaining a compound of general formula (VII):
Figure BDA0002726826650000202
wherein R'2Selected from-OH,
Figure BDA0002726826650000203
5) reacting-NO in the compounds of the general formulae (IV) - (VII)2At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure BDA0002726826650000204
wherein R is as defined in claim 1;
when R is
Figure BDA0002726826650000205
When the compound is not substituted by fluorine-containing compounds;
when R is1Is composed of
Figure BDA0002726826650000211
The method also comprises the following reactions:
Figure BDA0002726826650000212
when R is2Is composed of
Figure BDA0002726826650000213
The method also comprises the following reactions:
Figure BDA0002726826650000214
in the present application, the compounds of formula (ii) are commercially available or can be prepared synthetically, and the present application is not limited thereto. Illustratively, the compounds of formula (ii) may be prepared by:
1) reacting 2, 4-dinitroaniline and 5-bromo-2, 4-dichloropyrimidine in an organic solvent under an alkaline condition at the temperature of 60-80 ℃ for 8-14 hours to obtain a compound 62;
Figure BDA0002726826650000215
2) reducing the nitro group in the compound 62 obtained in the step 1) to obtain a compound 63;
3) connecting acetyl on the amino group in the compound 63 obtained in the step 2) to obtain a compound (namely a compound 65) of the formula (II);
Figure BDA0002726826650000221
the organic solvent used in the preparation of the compound of formula (ii) is not limited as long as the object of the present invention can be achieved, and may be selected from DMF and THF, for example.
In step 2), the nitro group reduction and the amino group-to-acetyl group-linking in the compound 62 can be performed by methods commonly used in the art, which are not limited herein, for example, the nitro group reduction can be performed by hydrogenation, for example, Pd/C can be used as a catalyst, and H can be reacted with H2Obtained by reaction or obtained by reaction with iron powder ammonium chloride; the amino-linked acetyl group can be obtained by reaction with acetyl chloride under basic conditions, for example in triethylamine solution or potassium carbonate solution.
In this application, a fluorine-containing compound is used to replace-NO in the precursor compound2At least one of-OH or-OTs, the fluorine-containing compound may be selected from:
Figure BDA0002726826650000222
or alkali metal fluorides, in which case, as a rule
Figure BDA0002726826650000223
React with-OH in the precursor compound to
Figure BDA0002726826650000224
To be provided with
Figure BDA0002726826650000225
and-NO2reduced-NH2React to form
Figure BDA0002726826650000226
-F is obtained by reacting an alkali metal fluoride, which may be selected from NaF or KF, with-OTs;
in some embodiments of the present application, when at least one fluorine in the compound is substituted with a fluorine18When F is substituted, it is possible to use18F-labelled compound with said precursor compound, preferably said compound18The F-labelled compound may be selected from
Figure BDA0002726826650000231
Or K18F; accordingly, it is common to
Figure BDA0002726826650000232
React with-OH in the precursor compound to
Figure BDA0002726826650000233
To be provided with
Figure BDA0002726826650000234
and-NO2reduced-NH2React to form
Figure BDA0002726826650000235
With K18F obtained by reaction with-OTs18F。
The inventor finds in research that the reaction flow is simple by adopting the preparation method disclosed by the application; by first synthesizing a precursor compound and then by reaction with a fluorine-containing compound or with a fluorine-containing compound18F-labeled fluorine-containing compound, namely the targeting FAK of the application can be obtainedCompound (I) or (II)18The F-labeled compound targeting FAK has flexible preparation method; in addition, by adopting the reaction process, no radioactive isotope exists in the synthesis process of the precursor compound, so that the synthesis process is safer; the radioactive isotope is added in the later period of the reaction, so that the half-life loss of the radioactive isotope is reduced.
A third aspect of the present application provides a precursor compound for the preparation of a compound as provided in the first aspect of the present application, selected from the following compounds:
Figure BDA0002726826650000236
Figure BDA0002726826650000241
Figure BDA0002726826650000251
in a fourth aspect, the present application provides the use of a compound of the first aspect of the present application in the manufacture of a medicament for the treatment of a tumour. The inventor finds that the FAK-targeting compound has high affinity with FAK and has a certain inhibition effect on FAK activity, so that the FAK-targeting compound can inhibit the growth, metastasis and the like of tumors, and can be used for preparing tumor treatment medicines.
The fifth aspect of the present application provides18The use of F-labeled FAK-targeting compounds in the preparation of tumor diagnostic imaging agents. The inventor finds in research that FAK is highly expressed in tumor cells, and the FAK is obtained through the method18The F-labeled compound targeting FAK can be specifically combined with FAK, so that the F-labeled compound can be enriched and combined in tumors18F label, which can be used as an imaging agent for tumor diagnosis, preferably an imaging agent for early diagnosis of tumors.
The type of tumor is not limited in this application, and for example, the tumor may be brain and Central Nervous System (CNS) cancer, head and neck cancer, renal cancer, ovarian cancer, pancreatic cancer, lung cancer, lymphoma, myeloma, sarcoma, breast cancer, prostate cancer, and the like. Exemplary brain and central CNS cancers include medulloblastoma, oligodendroglioma, atypical teratoid/rhabdoid tumor, choroid plexus cancer, choroid plexus papilloma, ependymoma, glioblastoma, meningioma, glioma, oligodendroastrocytoma, oligodendroglioma, and pineoblastoma. Exemplary ovarian cancers include clear cell ovarian adenocarcinoma, endometrioid ovarian adenocarcinoma, and serous ovarian adenocarcinoma. Exemplary pancreatic cancers include pancreatic ductal adenocarcinoma and pancreatic endocrine tumors. Exemplary sarcomas include chondrosarcoma, soft tissue clear cell sarcoma, ewing's sarcoma, gastrointestinal stromal tumor, osteosarcoma, rhabdomyosarcoma, and unspecified (NOS) sarcoma.
The tumor in the present application may also be a rare disease tumor body, such as pleural mesothelioma, jugular glomus tumor, neurofibroma, and the like.
In a fifth aspect, the present application provides a pharmaceutical composition comprising a compound provided in the first aspect of the present application.
Preparation example 1 organic Synthesis of Compound 79 and Compound 80
The synthetic route is as follows:
Figure BDA0002726826650000261
to a solution of 5-bromo-2, 4-dichloropyrimidine (compound 60) (25.0g,111.1mmol,1equiv) in THF (200mL) were added a solution of 2, 4-dinitroaniline (compound 61) (24.4g,133.3mmol,1.2equiv) in THF (200mL) and potassium carbonate (18.4g,133.3mmol,1.2equiv), and the mixture was heated to 70 ℃ to react overnight. After the reaction was completed, the potassium carbonate was filtered off, and washed with ethyl acetate (50mL × 3 times). The organic phase was collected and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (petroleum ether/ethyl acetate 10/1-5/1) was prepared at medium pressure to afford compound 62(21.9g, yellow solid, 50.8% yield);
1H NMR(400MHz,CDCl3,δppm):11.33(s,1H),9.32(d,J＝9.2Hz,1H),9.21(s,1H),8.59(s,2H).
to a solution of compound 62(20.0g,53.7mmol,1equiv) in tetrahydrofuran (100mL) and methanol (100mL) was added iron powder (14.9g,268.5mmol,5equiv) and a solution of ammonium chloride (14.3g,268.5mmol,5equiv) in water (40mL), and the mixture was heated to 80 ℃ for 4 h. After the reaction was completed, the reaction mixture was filtered while hot and washed with methanol (50mL × 3 times). The organic phase was collected and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 63(15.2g, black solid, 91.2% yield);
1H NMR(400MHz,DMSO-d6,δppm):8.45(s,1H),8.22(s,1H),6.58(dd,J＝3.7Hz,5.3Hz,1H),5.93(s,1H),5.81(m,1H),4.77(s,2H),4.54(s,2H).
13C NMR(100MHz,DMSO-d6,δppm):160.34,158.71,157.45,148.89,145.57,129.19,112.30,103.79,101.00.
ESI-MS:m/z 313.9800(M+H)+
to a solution of compound 63(15.0g,48.1mmol,1equiv) in anhydrous THF (200mL) at 0 ℃ was slowly added a solution of acetyl chloride (compound 64) (9.2g,120.2mmol,2.5equiv) diluted in anhydrous THF (50mL), and the mixture was reacted at 0 ℃ for 5 hours. After the reaction was completed, water (200mL) was added to quench the reaction, and extraction was performed with ethyl acetate (100mL × 3 times). The organic phases were collected, concentrated by rotary evaporation and separated on a medium pressure preparative Flash silica gel column (dichloromethane/methanol-20/1 to 10/1) to give compound 65(12.9g, yellow solid, 67.8% yield);
1H NMR(400MHz,DMSO-d6,δppm):10.03(s,1H),9.95(s,1H),8.80(s,1H),8.37(s,1H),7.78(s,1H),7.42(m,2H),2.05(d,J＝7.1Hz,6H),.
13C NMR(100MHz,DMSO-d6,δppm):169.98,168.82,158.75,158.33,158.16,137.88,132.83,127.56,125.52,116.37,114.86,104.22,24.43,23.59.
ESI-MS:m/z 398.0010(M+H)+
to a solution of compound 65(10.0g,25.2mmol,1equiv) in DMF (300mL) were added compound 78(4.6g,30.2mmol,1.2equiv) and p-toluenesulfonic acid (1.3g,7.6mmol,0.3equiv), and the reaction was stirred at 100 ℃ for 5 h. After completion of the reaction, the reaction mixture was poured into 200mL of water, followed by extraction with ethyl acetate (50mL × 3 times). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered, and the concentrated filtrate was rotary-evaporated, and separated by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1 to 5/1) to obtain compound 79(10.3g, red solid, yield 79.2%);
1H NMR(400MHz,DMSO-d6,δppm):10.37(s,1H),9.99(d,J＝2.2Hz,2H),9.29(s,1H),8.15(d,J＝3.6Hz,2H),8.04(s,1H),7.68(m,2H),7.53(d,J＝5.8Hz,1H),7.30(d,J＝6.1Hz,1H),6.86(d,J＝6.0Hz,1H),2.04(d,J＝6.6Hz,6H).
13C NMR(100MHz,DMSO-d6,δppm):170.06,168.78,158.54,157.27,137.31,136.14,132.10,127.65,127.24,119.71,116.69,115.28,114.68,24.54,23.54.
ESI-HRMS m/z calculated for C20H19BrN7O5+516.0626,found 516.0624[M+H]+
to a solution of compound 79(500mg,0.97mmol,1equiv) in DMF (6mL) was added potassium carbonate (200mg,1.45mmol,1.5equiv), a solution of FETos (423mg,1.94mmol,2equiv) in DMF (5mL), and the mixture was heated to 80 ℃ for 5 hours. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 80(487mg, red brown solid, 89.6% yield);
1H NMR(600MHz,DMSO-d6,δppm):10.01(s,2H),9.44(s,1H),8.20(s,1H),8.16(s,1H),7.99(s,1H),7.73(d,J＝14.8Hz,1H),7.66(s,1H),7.49(d,J＝12.9Hz,1H),7.35(d,J＝13.0Hz,1H),7.12(d,J＝13.7Hz,1H),4.74(t,J＝2.0Hz,1H),4.62(t,J＝5.2Hz,1H),4.34(t,J＝3.9Hz,1H),4.26(t,J＝3.9Hz,1H),2.04(d,J＝5.1Hz,6H).
13C NMR(100MHz,DMSO-d6,δppm):170.03,168.88,162.83,158.34,157.47,145.48,139.86,137.48,134.74,132.43,128.02,125.01,116.84,116.34,115.15,114.79,83.29,81.62,69.73,69.54,24.52,23.58.
ESI-HRMS m/z calculated for C22H22BrFN7O5 +562.0845,found 562.0848[M+H]+
preparation example 2 organic Synthesis of Compound 83 and Compound 84
The synthetic route is as follows:
Figure BDA0002726826650000291
compound 79 was obtained according to the method of preparation example 1;
to a solution of compound 79(500mg,0.97mmol,1equiv) in DMF (6mL) was added potassium carbonate (200mg,1.45mmol,1.5equiv), a solution of compound 81(911mg,1.94mmol,2equiv) in DMF (5mL), and the mixture was heated to 60 ℃ for 3 hours. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1 to 5/1) was prepared at medium pressure to afford compound 82(505mg, yellow solid, 64.1% yield);
1H NMR(600MHz,DMSO-d6,δppm):10.02(s,1H),9.99(s,1H),9.43(s,1H),8.20(s,1H),8.16(s,1H),7.97(s,1H),7.76-7.73(m,3H),7.62(s,1H),7.49(d,J＝8.2Hz,1H),7.39-7.38(m,3H),7.06(d,J＝9.5Hz,1H),4.30(dd,J＝2.0Hz,10.6Hz,1H),4.16-4.11(m,4H),4.05-4.02(m,1H),2.32(s,3H),2.04(d,J＝13.9Hz,6H),1.25(d,J＝13.4Hz,6H).
ESI-HRMS m/z calculated for C34H37BrN7O10S+814.1501,found 814.1497[M+H]+
to a solution of compound 82(100mg,0.12mmol,1equiv) in DMF (5mL) were added potassium carbonate (2mg,0.01mmol,0.1equiv), Kryptofix 222(CAS No. 23978-09-8, hereinafter abbreviated as K2.2.2) (45mg,0.12mmol,1equiv) and KF (14mg,0.24mmol,2equiv), and the mixture was heated to 100 ℃ for 1 hour. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1 to 5/1) was prepared at medium pressure to give compound 83(71mg, yellow solid, 90.1% yield);
1H NMR(600MHz,CD3OD,δppm):8.07(s,1H),7.93(s,1H),7.68(d,J＝2.0Hz,1H),7.59(dd,J＝2.1Hz,9.1Hz,1H),7.51(d,J＝8.7Hz,1H),7.40(d,J＝2.0Hz,8.1Hz,1H),7.06(d,J＝9.1Hz,1H),4.31-4.29(m,1H),4.25-4.19(m,3H),3.84-3.81(m,1H),3.76-3.73(m,1H),2.14(s,3H),2.11(s,3H),1.40(s,3H),1.38(s,3H).
ESI-HRMS m/z calculated for C27H30BrFN7O7 +662.1369,found 662.1359[M+H]+
to a solution of compound 83(20mg,0.03mmol,1equiv) in DMF (3mL) was added 1M hydrochloric acid (200. mu.L), and the mixture was heated to 100 ℃ for reaction for 20 min. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 84(16mg, yellow solid, 85.6% yield);
1H NMR(600MHz,CD3OD,δppm):8.09(s,1H),7.87(s,1H),7.65(s,1H),7.56(d,J＝9.7Hz,1H),7.48(d,J＝7.9Hz,1H),7.36(d,J＝9.2Hz,1H),7.09(d,J＝8.9Hz,1H),4.77-4.44(m,2H),4.21-4.12(m,2H),4.01-3.98(m,2H),2.14(d,J＝8.2Hz,6H).
ESI-HRMS m/z calculated for C24H26BrFN7O7 +622.1056,found 622.1060[M+H]+
preparation example 3 organic Synthesis of Compound 75
The synthetic route is as follows:
Figure BDA0002726826650000311
compound 65 was prepared according to the procedure of preparation example 1;
to a solution of N-acetyl-. beta. -alanine (compound No. 67) (5.0g,38.1mmol,1equiv) in dichloromethane (100mL) were added HATU (17.3g,45.7mmol,1.2equiv) and DIPEA (14.7g,114.3mmol,3equiv), and the mixture was stirred at room temperature for 1 h. 2-amino-4-nitrophenol (Compound 66) (7.0g,45.7mmol,1.2equiv) was added and stirred at room temperature overnight. The solid precipitated, was filtered and washed with dichloromethane (50mL x 3) to give compound 68(8.9g, yellow solid, 88.0% yield);
1H NMR(400MHz,DMSO-d6,δppm):9.40(s,1H),8.93(s,1H),7.90(t,J＝9.0Hz,2H),6.99(d,J＝8.6Hz,1H),3.30(d,J＝5.0Hz,2H),2.57(s,2H),1.76(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):176.04,174.72,159.54,144.49,132.24,126.04,122.22,120.20,41.70,40.52,28.07.
ESI-HRMS m/z calculated for C11H14N3O5 +268.0928,found 268.0930[M+H]+.
to a solution of compound 68(5.0g,18.7mmol,1equiv) in tetrahydrofuran (50mL) and methanol (50mL) was added a solution of iron powder (5.2g,93.5mmol,5equiv) and ammonium chloride (5.0g,93.5mmol,5equiv) in water (10mL), and the mixture was heated to 80 ℃ for reaction for 3 h. After the reaction was completed, the reaction mixture was filtered while hot and washed with methanol (50mL × 3 times). The organic phase was collected and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 69(3.9g, black solid, 89.2% yield);
1H NMR(400MHz,DMSO-d6,δppm):9.24(s,1H),8.57(s,1H),7.90(s,1H),6.86(s,1H),6.49(d,J＝8.2Hz,1H),6.13(d,J＝8.1Hz,1H),4.49(s,2H),3.20(d,J＝5.7Hz,2H),2.45(d,J＝6.4Hz,1H),1.70(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):170.29,169.69,141.44,139.21,126.96,117.35,111.41,108.99,36.46,35.77,23.02.
ESI-HRMS m/z calculated for C11H15N3NaO3 +260.1006,found 260.1003[M+H]+.
to a solution of compound 65(5.0g,12.5mmol,1equiv) in DMF (100mL) was added compound 69(4.4g,18.7mmol,1.5equiv) and p-toluenesulfonic acid (0.6g,3.7mmol,0.3equiv), and the reaction was stirred at 100 ℃ for 5 h. After completion of the reaction, the reaction mixture was poured into 200mL of water, followed by extraction with ethyl acetate (50mL × 3 times). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol-20/1 to 5/1) was prepared at medium pressure to give compound 74(5.5g, white solid, 74.7% yield);
1H NMR(600MHz,DMSO-d6,δppm):10.00(s,1H),9.98(s,1H),9.27(s,1H),9.17(s,1H),8.95(s,1H),8.06(s,1H),8.04(s,1H),7.91(s,1H),7.88(t,J＝5.2Hz,1H),7.64-7.59(m,2H),7.31(dd,J＝1.9Hz,8.7Hz,1H),7.21(dd,J＝3.5Hz,9.9Hz,1H),6.60(d,J＝8.7Hz,1H),3.25-3.23(m,2H),2.51(t,J＝5.7Hz,2H),2.04(s,3H),2.02(s,3H),1.75(s,3H)。
ESI-HRMS m/z calculated for C25H28BrN8O5 +599.1361,found 599.1359[M+H]+.
to a solution of compound 74(100mg,0.17mmol,1equiv) in DMF (2mL) was added potassium carbonate (34mg,0.25mmol,1.5equiv) and sodium iodide (3mg,0.02mmol,0.1equiv), a solution of FETos (74mg,0.34mmol,2equiv) in DMF (1mL) was added, and the reaction was carried out at 70 ℃ overnight. Filtration and concentration of the filtrate, medium pressure Flash silica gel column separation (dichloromethane/methanol 20/1 to 5/1) afforded compound 75(61mg, white solid, 55.7% yield);
1H NMR(600MHz,DMSO-d6,δppm):9.98(s,2H),9.06(s,1H),8.85(s,1H),8.08(d,J＝9.1Hz,2H),7.85(s,2H),7.60-7.58(m,2H),7.37(d,J＝8.4Hz,1H),7.32(d,J＝8.2Hz,1H),6.78(d,J＝8.8Hz,1H),4.75(t,J＝3.5Hz,1H),4.67(t,J＝3.3Hz,1H),4.18(t,J＝3.6Hz,1H),4.13(t,J＝3.4Hz,1H),3.25(d,J＝6.3Hz,2H),2.48(m,2H),2.04(s,3H),2.03(s,3H),1.74(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):170.09,169.82,168.91,167.85,158.95,157.57,157.22,144.74,137.06,134.49,128.06,127.87,127.64,116.99,116.78,115.68,115.39,113.85,83.47,82.37,69.48,36.80,35.80,24.59,23.63,23.19.
ESI-HRMS m/z calculated for C27H31BrFN8O5 +645.1579,found 645.1581[M+H]+.
preparation example 4 organic Synthesis of Compound 76 and Compound 77
The synthetic route is as follows:
Figure BDA0002726826650000331
compound 65 was prepared according to the procedure of preparation example 1.
To a solution of N-acetylethylenediamine (compound 71) (5.0g,49.0mmol,1equiv) in dichloromethane (100mL) were added HATU (22.2g,58.8mmol,1.2equiv) and DIPEA (18.9g,147.0mmol,3equiv), and the mixture was stirred at room temperature for 1 h. 5-Nitrosalicylic acid (compound 70) (10.2g,58.8mmol,1.2equiv) was added and stirred at room temperature overnight. The solid precipitated, was filtered and washed with dichloromethane (50mL x 3) to give compound 72(6.6g, yellow solid, 91.2% yield);
1H NMR(600MHz,DMSO-d6,δppm):13.63(s,1H),9.19(s,1H),8.81(d,J＝1.9Hz,1H),8.23(d,J＝9.3Hz,1H),7.95(s,1H),7.07(d,J＝9.0Hz,1H),3.34(dd,J＝5.8Hz,11.7Hz,2H),3.22(dd,J＝6.1Hz,12.1Hz,2H),1.77(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):175.08,172.58,171.23,144.28,134.08,130.49,124.02,121.44,43.36,28.10.
ESI-HRMS m/z calculated for C11H14N3O5 +268.0928,found 268.0930[M+H]+.
to a solution of compound 72(5.0g,18.7mmol,1equiv) in tetrahydrofuran (50mL) and methanol (50mL) was added a solution of iron powder (5.2g,93.5mmol,5equiv) and ammonium chloride (5.0g,93.5mmol,5equiv) in water (10mL), and the mixture was heated to 80 ℃ for reaction for 3 h. After the reaction was completed, the reaction mixture was filtered while hot and washed with methanol (50mL × 3 times). The organic phase was collected and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 73(3.8g, black solid, 86.3% yield);
1H NMR(400MHz,DMSO-d6,δppm):11.34(s,1H),8.66(s,1H),8.02(s,1H),7.01(s,1H),6.68-6.61(m,2H),4.51(s,2H),3.17-3.14(m,4H),1.78(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):169.93,169.33,151.13,140.79,121.11,117.88,116.21,112.85,39.28,38.67,23.05.
ESI-HRMS m/z calculated for C11H15N3NaO3 +260.1006,found 260.1003[M+H]+；
to a solution of compound 65(5.0g,12.5mmol,1equiv) in DMF (100mL) were added compound 73(4.4g,18.7mmol,1.5equiv) and p-toluenesulfonic acid (0.6g,3.7mmol,0.3equiv), and the reaction was stirred at 100 ℃ for 5 h. After completion of the reaction, the reaction mixture was poured into 200mL of water, followed by extraction with ethyl acetate (50mL × 3 times). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol-20/1 to 5/1) was prepared at medium pressure to give compound 76(6.1g, white solid, 82.3% yield);
1H NMR(600MHz,DMSO-d6,δppm):11.89(s,1H),10.01(s,1H),9.97(s,1H),8.95(s,1H),8.64(d,J＝5.4Hz,1H),8.08-8.07(m,2H),7.93(t,J＝5.5Hz,1H),7.75(s,1H),7.64-7.62(m,2H),7.44(dd,J＝2.1Hz,9.0Hz,1H),7.20(d,J＝8.0Hz,1H),6.69(d,J＝8.6Hz,1H),3.27-3.26(m,2H),3.17(dd,J＝6.0Hz,12.1Hz,2H),2.04(s,3H),2.01(s,3H),1.75(s,3H).
13C NMR(600MHz,DMSO-d6,δppm):170.08,168.98,168.77,159.20,157.58,156.87,155.20,136.80,131.90,131.40,127.66,127.12,121.20,117.20,116.58,115.92,115.40,93.26,38.56,24.52,23.46,23.14.
ESI-HRMS m/z calculated for C25H28BrN8O5 +599.1361,found 599.1359[M+H]+.
to a solution of compound 76(100mg,0.17mmol,1equiv) in DMF (2mL) was added potassium carbonate (34mg,0.25mmol,1.5equiv) and sodium iodide (3mg,0.02mmol,0.1equiv), a solution of FETos (74mg,0.34mmol,2equiv) in DMF (1mL) was added, and the reaction was carried out at 70 ℃ overnight. Filtration and concentration of the filtrate, medium pressure Flash silica gel column separation (dichloromethane/methanol 20/1 to 5/1) afforded compound 77(80mg, white solid, 73.5% yield);
1H NMR(600MHz,DMSO-d6,δppm):10.00(s,1H),9.97(s,1H),9.20(s,1H),8.10-8.08(m,3H),7.89(t,J＝5.3Hz,1H),7.74(s,1H),7.70(d,J＝8.7Hz,1H),7.60(s,1H),7.57(d,J＝8.2Hz,1H),7.41(d,J＝8.4Hz,1H),6.87(d,J＝8.5Hz,1H),4.81(t,J＝3.2Hz,1H),4.73(t,J＝3.4Hz,1H),4.29(t,J＝3.2Hz,1H),4.24(t,J＝3.3Hz,1H),3.30-3.29(m,2H),3.16(dd,J＝6.0Hz,12.0Hz,2H),2.04(s,3H),2.03(s,3H),1.76(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):170.02,168.87,165.29,158.72,157.51,157.29,150.97,137.12,134.73,132.14,127.42,123.81,123.64,122.09,117.00,115.26,114.20,83.19,82.09,69.16,69.03,38.84,24.50,23.58,23.10.
ESI-HRMS m/z calculated for C27H31BrFN8O5 +645.1579,found 645.1581[M+H]+.
preparation example 5 organic Synthesis of Compound 95
The synthetic route is as follows:
Figure BDA0002726826650000361
compound 79 was obtained by the method of reference preparation example 1.
To a solution of 6-fluoronicotinic acid (compound 92) (15.0g,106.3mmol,1equiv) in 1, 4-dioxane (500mL) was added 2,3,5, 6-tetrafluorophenol (compound 86) (17.6g,106.3mmol,1equiv) and dicyclohexylcarbodiimide DCC (24.1g,116.9mmol,1.1equiv) at room temperature, and the mixture was stirred at room temperature overnight. After completion of the reaction, the by-product DCU was filtered off, the filtrate was concentrated by rotary evaporation, and subjected to Flash silica gel column separation under medium pressure (petroleum ether/ethyl acetate: 20/1 to 5/1) to obtain compound 93(24.3g, white solid, yield 79.2%).
1H NMR(400MHz,CDCl3,δppm):9.08(s,1H),8.57(m,1H),7.13(m,2H).
To a solution of compound 79(10.0g,19.4mmol,1equiv) in tetrahydrofuran (50mL) and methanol (50mL) was added a solution of iron powder (5.4g,97.0mmol,5equiv) and ammonium chloride (5.1g,97.0mmol,5equiv) in water (20mL), and the mixture was heated to 80 ℃ for reaction for 2 h. After the reaction was completed, the reaction mixture was filtered while hot and washed with methanol (50mL × 3 times). The organic phase was collected and the filtrate was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 94(8.4g, white solid, 89.2% yield);
1H NMR(400MHz,DMSO-d6,δppm):9.99(s,2H),8.70(s,1H),8.48(s,1H),8.05(d,J＝16.9Hz,2H),7.67(d,J＝6.8Hz,2H),7.39(d,J＝8.7Hz,1H),6.75(s,1H),6.58(d,J＝8.2Hz,1H),6.41(d,J＝8.3Hz,1H),4.22(m,2H),2.07(d,J＝8.2Hz,6H).
13C NMR(100MHz,DMSO-d6,δppm):169.95,168.71,158.93,157.30,156.86,139.60,136.76,136.48,133.01,131.65,127.71,127.36,116.69,115.33,114.51,108.79,107.36,92.38,24.42,23.42.
ESI-MS:m/z 486.0881(M+H)+
to a solution of compound 94(1.0g,2.0mmol,1equiv) in DMSO (10mL), compound 93(1.1g,4.0mmol,2equiv) and DIPEA (0.2g,1.5mmol,0.75equiv) were added, and the mixture was heated to 60 ℃ for 1 hour. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 95(0.9g, green solid, 75.0% yield);
1H NMR(400MHz,DMSO-d6,δppm):10.01(s,1H),9.87(s,1H),9.72(s,1H),9.13(s,1H),9.04(s,1H),8.75(s,1H),8.44(t,J＝4.8Hz,1H),8.09(s,2H),7.63(m,3H),7.30(m,3H),6.67(d,J＝5.8Hz,1H),2.05(s,3H),1.97(s,3H).
13C NMR(100MHz,DMSO-d6,δppm):170.28,168.85,159.09,157.66,157.14,148.63,48.38,145.74,142.51,142.42,136.94,132.82,131.75,129.56,127.86,127.40,125.25,118.86,116.95,116.32,115.60,110.50,110.18,109.86,24.60,23.68.
ESI-MS:m/z 609.1000(M+H)+
preparation example 6 Synthesis of Compound 102 and Compound 103
The synthetic route is as follows:
Figure BDA0002726826650000371
Figure BDA0002726826650000381
compound 79 was obtained by the method of reference preparation example 1.
Compound 93 was obtained according to the method of preparation example 5.
To a solution of compound 79(1.0g,1.9mmol,1equiv) in DMF (50mL) was added N, N-dimethyl-bromoacetamide (compound 96) (0.6g,3.8mmol,2equiv), potassium carbonate (0.5g,3.8mmol,2equiv) and potassium iodide (33.2mg,0.2mmol,0.1equiv), and the mixture was heated to 50 ℃ for 3 h. At the end of the reaction, water (100mL) was added to precipitate a solid which was collected by filtration and dried to give compound 97(0.8g, yellow solid, yield 72.3%);
1H NMR(400MHz,DMSO-d6,δppm):10.02(s,2H),9.35(s,1H),8.15(s,1H),8.10(s,1H),7.94(s,1H),7.63(d,J＝7.7Hz,1H),7.57(s,1H),7.46(d,J＝8.8Hz,1H),7.31(d,J＝7.6Hz,1H),6.96(d,J＝8.9Hz,1H),4.87(s,2H),2.89(s,3H),2.73(s,3H),1.99(d,J＝5.6Hz,6H).
13C NMR(100MHz,DMSO-d6,δppm):174.79,168.85,166.96,158.40,157.37,145.79,139.67,137.37,134.39,130.18,124.91,117.00,116.12,115.34,114.88,67.32,36.00,35.51,24.50,23.55.
ESI-MS:m/z 601.1156(M+H)+
compound 97(100mg,0.16mmol,1equiv) was dissolved in a mixed solution of 5mL of tetrahydrofuran and 5mL of methanol, and a solution of iron powder (22.4mg,0.4mmol,2.5equiv) and ammonium chloride (21.2mg,0.4mmol,2.5equiv) in water (1mL) was added, and the temperature was raised to 80 ℃ for reaction for 3 hours. After the reaction was completed, the reaction mixture was filtered while hot and washed with methanol (10mL × 3 times). The organic phase was collected, the filtrate was concentrated by rotary evaporation and Flash silica gel column separation was prepared at medium pressure (dichloromethane/methanol-20/1-5/1) to give compound 98(80mg, white solid, 87.7% yield);
1H NMR(400MHz,DMSO-d6,δppm):10.00(s,2H),8.83(s,1H),8.07(d,J＝6.9Hz,2H),7.63(d,J＝7.3Hz,2H),7.42(d,J＝8.6Hz,1H),6.80(s,1H),6.66(d,J＝8.4Hz,1H),6.55(s,1H),4.61(s,2H),4.56(s,2H),2.95(s,3H),2.82(s,3H),2.06(d,J＝8.0Hz,6H).
13C NMR(100MHz,DMSO-d6,δppm):175.03,170.05,168.85,168.46,158.88,157.41,157.06,141.41,138.54,136.95,135.20,131.93,127.87,127.60,116.90,115.31,114.17,108.42,106.85,68.29,36.12,35.51,25.02,24.50.
ESI-MS:m/z 571.1415(M+H)+
to a solution of Fmoc-2-amino-5- (tert-butoxy) -5-oxopentanoic acid (compound 99) (90mg,0.21mmol,1equiv) in anhydrous DMF (3mL) at 0 deg.C was added a solution of DIPEA (32.5mg,0.25mmol,1.2equiv) and HATU (79.8mg,0.21mmol,1equiv) in anhydrous DMF (3mL) and stirred at 0 deg.C for 0.5 h. A solution of compound 98(96.9mg,0.17mmol,0.8equiv) in anhydrous DMF (3mL) was added and stirring continued for 2 h. After the reaction was completed, water (50mL) was added to precipitate a solid as a crude product, which was directly subjected to the next reaction without purification to obtain a crude product of Compound 100 (70mg, white solid, yield 34.1%).
To a solution of compound 100(50mg,0.05mmol,1equiv) in tetrahydrofuran (3mL) was added a solution of tetra-n-butylammonium fluoride in 1M tetrahydrofuran (0.1mL, 0.1mmol,2equiv) and reacted at room temperature for 0.5 h. After the reaction is finished, the reaction solution is concentrated by rotary evaporation, Flash silica gel column separation is prepared at medium pressure (dichloromethane/methanol is 20/1-5/1), and the compound 101(34.3mg, white solid and 91.1 percent of yield) is obtained;
1H NMR(600MHz,DMSO-d6,δppm):10.46(s,1H),10.29(s,1H),10.20(s,1H),9.08(s,1H),8.18(s,1H),8.11(s,1H),8.07(s,1H),7.63(d,J＝7.7Hz,1H),7.58(s,1H),7.49(d,J＝8.5Hz,1H),7.29(dd,J＝1.9Hz,8.9Hz,1H),6.79(d,J＝8.8Hz,1H),4.84(s,2H),3.37(m,1H),2.96(s,3H),2.80(s,3H),2.32(t,J＝7.6Hz,2H),2.06(s,3H),2.04(s,3H),1.98(m,1H),1.70(m,1H),1.34(s,9H).
13C NMR(600MHz,DMSO-d6,δppm):172.94,172.60,170.09,168.93,168.10,158.93,157.46,156.93,143.57,136.99,134.49,131.48,129.18,128.30,127.60,117.09,115.79,115.53,113.87,112.66,93.21,80.07,68.26,55.12,36.11,35.52,30.09,28.29,24.46,23.62,23.40.
ESI-MS:m/z 756.2460(M+H)+
to a solution of compound 101(100mg,0.13mmol,1equiv) in DMF (3mL) were added compound 93(37.5mg,0.13mmol,1equiv) and DIPEA (50.3mg,0.39mmol,3equiv), and the mixture was heated to 60 ℃ for 1 h. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to afford compound 102(97.0mg, white solid, 85.0% yield);
1H NMR(600MHz,CD3OD,δppm):8.75(s,2H),8.42(t,J＝9.9Hz,2H),8.01(s,2H),7.65(d,J＝8.9Hz,1H),7.58(d,J＝2.0Hz,1H),7.42(dd,J＝2.1Hz,8.2Hz,1H),7.30(dd,J＝2.1Hz,9.0Hz,1H),7.15(dd,J＝1.9Hz,8.3Hz,1H),6.88(d,J＝8.9Hz,1H),4.79(m,3H),2.97(s,3H),2.84(s,3H),2.46(t,J＝7.6Hz,2H),2.34(m,1H),2.12(s,3H),2.10(s,3H),2.01(s,1H),1.40(s,9H).
13C NMR(600MHz,CD3OD,δppm):172.73,171.22,170.46,170.11,169.26,165.92,164.33,158.69,157.26,156.59,147.72,147.61,144.69,141.50,136.25,134.53,131.21,129.51,128.28,127.28,117.83,117.09,116.14,115.04,114.33,109.26,109.01,92.76,80.58,68.57,54.46,34.84,34.51,29.40,27.01,22.62,22.39,21.68.
ESI-MS:m/z 879.2580(M+H)+
to a solution of compound 102(100mg,0.11mmol,1equiv) in DMF (3mL) was added TFA (12.9mg,0.11mmol,1equiv), and the mixture was heated to 60 ℃ for 1 hour. The reaction was concentrated by rotary evaporation and Flash silica gel column separation (dichloromethane/methanol 20/1-5/1) was prepared at medium pressure to give compound 103(68.8mg, white solid, 76.1% yield);
1H NMR(600MHz,CD3OD,δppm):8.72(s,1H),8.42(t,J＝6.7Hz,1H),7.97(s,1H),7.92(s,1H),7.61(d,J＝8.7Hz,1H),7.56(s,1H),7.38(d,J＝8.6Hz,1H),7.25(d,J＝7.5Hz,1H),7.10(d,J＝8.6Hz,1H),6.84(d,J＝8.6Hz,1H),4.73(s,2H),4.62(d,J＝4.5Hz,1H),2.93(s,3H),2.80(s,3H),2.38-2.35(m,2H),2.20-2.07(m,8H).
ESI-HRMS m/z calculated for C35H37BrFN10O8 +823.1958,found 823.1953[M+H]+.
preparation example 7 Compound [ 2 ]18F]75、[18F]83 and [ 2 ]18F]84F-18 labeling and isolation and purification18F]Synthesis of FETos:
Figure BDA0002726826650000411
15mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 1mg of K2CO3Dissolved in 0.3mL of water,after mixing, it is captured on a QMA column18F-Leaching into a reaction flask, and adding N at 100 DEG C2Blowing the solvent in the reaction bottle to dry, then adding 0.5mL of anhydrous acetonitrile into the solvent, blowing the solvent to dry again, and repeating the process for three times to ensure that the water in the reaction bottle is fully removed; a solution of the first-step labeled precursor, 1, 2-bis-methylphenoxyethane (4mg), in anhydrous acetonitrile (0.3mL) was quickly added to the above reaction flask, sealed, and reacted at 110 ℃ for 10 min. After the reaction was complete, the reaction was quenched with acetonitrile: water 1:1 as mobile phase, flow rate 4mL/min, wavelength 254nm, C18 reversed phase semi-preparative column (Agela Technologies, 5 μm,
Figure BDA0002726826650000412
10X 250 mm). Product 2-, [ 2 ]18F]Fluoroethyl tosylate [ 2 ] (]18F]FETos) was 12 minutes.
[18F]75, synthesis:
Figure BDA0002726826650000413
2-, [ product of the previous step ]18F]Fluoroethyl tosylate [ 2 ] (]18F]FETos) was collected into a 100mL sterile vial and 50mL water was added. The diluted product solution was loaded onto a Sep-Pak C-18 column, N2The Sep-Pak C-18 column was air dried, the product on the Sep-Pak C-18 column was eluted with 3mL of diethyl ether into a sterile vial and dried at 40 ℃ with nitrogen flow. A solution of the second-step labeled precursor (compound 74, 4mg) in acetonitrile (0.4mL) was added thereto, and anhydrous potassium carbonate (1mg) was further added thereto, followed by uniform mixing and reaction at 120 ℃ for 20 minutes. The column was purified by semi-preparative column (Agela Technologies, 5 μm,
Figure BDA0002726826650000424
10X 250mm) liquid phase separation of the product. As shown in FIG. 1, the compound [ 2 ]18F]The retention time of the 75 liquid phase was 22.8 minutes, and the analysis of co-injection with the 75 liquid phase of the compound confirmed the radioactive compound [ 2 ]18F]75 accuracy.
[18F]83、[18F]84, synthesis:
Figure BDA0002726826650000421
[18F]83 Synthesis:
15mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 1mg of K2CO3Dissolving in 0.3mL water, and mixing to obtain 1.0mL Kryptofix 222/K2CO3An eluent; capturing on QMA column with the eluate18F-Leaching into a reaction flask, and adding N at 100 DEG C2Blowing the solvent in the reaction bottle to dry, then adding 0.5mL of anhydrous acetonitrile into the solvent, blowing the solvent to dry again, and repeating the process for three times to ensure that the water in the reaction bottle is fully removed; a solution of the first-step labeled precursor 82(4mg) in anhydrous DMF (0.3mL) was quickly added to the above reaction flask, sealed and reacted at 110 ℃ for 20 min. After the reaction was complete, a C18 reverse phase semi-preparative column (Agela Technologies, 5 μm,
Figure BDA0002726826650000422
10X 250mm) to obtain a radiolabeled compound18F]83。
[18F]84, synthesis:
compound [ 2 ] grafted to a Radio-HPLC liquid phase18F]83 adding 1M hydrochloric acid (200. mu.L), heating to 100 deg.C, and reacting for 20 min. C18 reversed phase semi-preparative columns (Agela Technologies, 5 μm,
Figure BDA0002726826650000423
10X 250mm) to obtain a radiolabeled compound18F]84。
As shown in FIG. 2, the compound [ 2 ]18F]83 has a liquid phase retention time of 8.4 minutes, and a liquid phase coinjection analysis with the compound 83 confirms the radioligand [ 2 ]18F]83 accuracy.
As shown in FIG. 3, the compound [ 2 ]18F]84 has a liquid phase retention time of 3.4 minutes, anThe liquid phase coinjection analysis with the compound 84 confirmed the radioligand [ 2 ]18F]84, accuracy.
Preparation example 8 Compound [ 2 ]18F]102 and [ 2 ]18F]103F-18 labelling and isolation purification
The synthetic route is as follows:
Figure BDA0002726826650000431
Figure BDA0002726826650000441
to a solution of 6-chloronicotinic acid (compound 85) (15.0g,95.5mmol,1equiv) in 1, 4-dioxane (500mL) was added 2,3,5, 6-tetrafluorophenol (compound 86) (15.8g,95.5mmol,1equiv) and dicyclohexylcarbodiimide DCC (21.6g,105.0mmol,1.1equiv) at room temperature, and stirred at room temperature overnight. After the reaction was completed, the by-product DCU was filtered off, the filtrate was concentrated by rotary evaporation, and subjected to Flash silica gel column separation under medium pressure (petroleum ether/ethyl acetate: 20/1 to 5/1) to obtain compound 87(22.7g, white solid, yield 78.2%).
1H NMR(400MHz,CDCl3,δppm):9.18(s,1H),8.41(d,J＝8.2Hz,1H),7.54(d,J＝8.3Hz,1H),7.12(m,1H).
To a solution of compound 87(0.5g,1.5mmol,1equiv) in anhydrous THF (3mL) was added a 2M solution of trimethylamine (compound 88) in tetrahydrofuran (2.5mL,5.0mmol,3.3equiv) at room temperature, and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration and washed with dichloromethane (50mL × 2). The precipitate was compound 89, which did not require further purification and did not affect the subsequent reaction. The precipitate was suspended in a solution of dichloromethane (5mL) and sonicated for 5 minutes. Trimethylsilyl trifluoromethanesulfonate (compound 90) (0.5mL,2.6mmol) was added thereto, and the mixture was vigorously stirred at room temperature overnight. Filtering, collecting concentrated filtrate, precipitating solid, washing solid with diethyl ether (50mL x 3) to obtain compound 91N+(0.2g, white solid, yield 28.5%).
1H NMR(400MHz,CD3OD,δppm):9.40(s,1H),8.93(d,J＝8.5Hz,1H),8.28(d,J＝8.6Hz,1H),7.58(m,1H),3.74(s,9H).
19F NMR(400MHz,CD3OD,δppm):-80.06(s,3F),-140.90(m,4F).
First 2mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 2mg of KHCO3Dissolving in 0.3mL water, and mixing to obtain 1.0mL Kryptofix 222/K2CO3An eluent; capturing on QMA column with the eluate18F-Leaching into a reaction flask, and adding N at 100 DEG C2Blowing the solvent in the reaction bottle by using air flow, adding 0.5mL of anhydrous acetonitrile into the solvent, blowing the solvent again, and repeating the process for three times to ensure that the moisture in the reaction bottle is fully removed; labeling the precursor Compound 91N+(8mg) of anhydrous acetonitrile/anhydrous t-butanol (2/80.3 mL) was quickly added to the above reaction flask, sealed, and reacted at 40 ℃ for 10 min. After the reaction was complete, acetonitrile (1mL) was added for dilution, drawn into a syringe and injected into a sterile penicillin vial via MCX Plus Sep-Pak at 60 ℃ N2Blow-drying with air, i.e., pure radiolabeled compound [ alpha ], [ beta ] -cyclodextrin18F]93。
2mg of the precursor (Compound 101 prepared by the method of preparation example 6) was dissolved in anhydrous DMSO (0.5mL) and added to the prepared Compound [ 2 ], [18F]Adding DIPEA (20 mu.L) into a small bottle of 93 penicillin, sealing, heating at 60 ℃ for 20min, adding water (10mL) for quenching after the reaction is finished, pumping the diluent into an activated C-18 column, drying the air, washing the product by using methanol (1mL) through the C-18 column, and directly purifying by using Radio-HPLC to obtain the radiolabeled compound18F]102。
The compound 2 grafted from Radio-HPLC18F]Transferring the 102 pure product into a sterile penicillin bottle, adding trifluoroacetic acid (300 mu L), sealing, heating at 60 ℃ for 20min, adding water (10mL) for quenching after the reaction is finished, pumping the diluent into an activated C-18 column, drying the air, washing the product through the C-18 column by using methanol (1mL), and directly purifying by using Radio-HPLC to obtain the radiolabeled compound [ 2 ]18F]103。
As shown in FIG. 4, the compound [ 2 ]18F]102 liquid phase ofThe retention time was 5.5 minutes, and the liquid phase coinjection analysis with the compound 102 confirmed that the radioligand [ 2 ]18F]102, accuracy of the measurement.
As shown in FIG. 5, the compound [ 2 ]18F]103 has a liquid phase retention time of 3.7 minutes, and a liquid phase coinjection analysis with the compound 103 confirms the radioligand [ 2 ]18F]103.
Experimental example 1 in vitro inhibition of FAK enzyme Activity and Selective inhibition of different kinase Activity
10 compounds prepared in the foregoing preparation examples 1 to 6 were used as standards to be evaluated in this experiment.
This test uses homogeneous time-resolved fluorescence-conjugated energy transfer from Cisbio: (
Figure BDA0002726826650000462
Method) for activity detection. FAK kinase was purchased from cana corporation; the detection kit is purchased from Cisbio company; assay plates and multifunctional plate readers were purchased from Perkin Elmer. In the assay plate, the enzyme, the biotin-labeled polypeptide substrate, ATP, and the assay compound are mixed and incubated for reaction. The compound concentration was 11 in total, and the final system concentration was from 10. mu.M to 0.17 nM. mu.L of the buffer reaction (50mM Hepes pH 7.5,1mM EDTA,10mM MgCl2, 0.01% Brij-35,25nM SEB,1mM DTT,0.7nM FAK, 1. mu.M biotin-TK peptide, 25. mu.M ATP) was incubated at 23 ℃ for 90 minutes. mu.L of stop solution (20mM EDTA, 0.67nM TK antibody, 50nM XL-665) was added and incubated at 23 ℃ for 60min with Envision reading. The inhibition of the compound was calculated from the data read by the instrument and then the IC was calculated using XLFIT 205 from IDBS in model 550The value is obtained.
TABLE 1 results of in vitro inhibition of FAK enzyme Activity by Compounds
Figure BDA0002726826650000461
Figure BDA0002726826650000471
Figure BDA0002726826650000481
GSK-2256098 (Shanghai drug Mingkude new drug development Co., Ltd.) is a FAK inhibitor in a second-phase clinical test, and the FAK kinase in-vitro inhibitory activity test was carried out using it as a positive control, and the results are shown in Table 1. The results in Table 1 show the FAK-IC of compounds 79, 77, 75, 95 and 10250The inhibition effect of the compounds on FAK is better than that of GSK-2256098;
in addition, in the field of drug development, according to the Rinski rule, the logarithm value (logP) of the lipid-water partition coefficient of the compound is generally required to be between-2 and 5, wherein the LogP has higher bioavailability in the metabolism process of about 0-2 in an organism, and the ClogP is directly calculated by introducing the structure of the compound through a ClogP module of ACD Labs Pro V10 software commonly used in the field and is similar to the LogP. From the results, it can be seen that the ClogP of the compounds of the present application was between-2 and 5, mostly between 0-2, and lower than that of the positive control GSK-2256098, indicating better oral availability of the compounds of the present application.
Experimental example 2 biodistribution experiment of F-18 radiopharmaceutical in S180 tumor-bearing mice
2.1 animal model establishment
Under aseptic conditions, disinfecting the underarm skin of a normal female Kunming mouse (18-22g) by alcohol; collecting well-grown S180 ascites cells (purchased from Shanghai Seifen Biotech Co., Ltd., product number ZY-M019), and diluting with normal saline to cell concentration of (1-5) × 1070.1mL of the cells were inoculated under the axillary skin of a female Kunming mouse.
The size of the tumor growing to 0.5-0.8cm in diameter (about one week in time) can be used for biodistribution experiments, namely S180 tumor-bearing mice.
2.2 in vivo distribution experiments in animal radioactivity
The [ 2 ] prepared in preparation example 7 purified by HPLC18F]75、[18F]83 and [ 2 ]18F]84 (10. mu. Ci, solvent)S180 tumor-bearing mice (18-22g, female, n-5) were injected via tail vein injection into 0.1mL of physiological saline containing 5% DMSO), the mice were sacrificed at 5min, 15min, 30min, 60min, 120min, and the hemorrhage, brain, heart, liver, spleen, lung, kidney, muscle, bone, intestine, stomach, S180 tumors and tail were dissected, the wet weight of each organ was measured and measured by γ -counter, and the uptake per tissue was finally expressed as% ID/g,% ID/g ═ ID/g ÷ 1%, where the radioactivity count (counts) of ID/g tissue divided by the tissue mass (mg) and 1% — the average of 1% ID per phase-tail radioactivity count/100.
2.3 discussion of results
[18F]75 biodistribution data in S180 tumor-bearing mice are shown in Table 2; [18F]83 biodistribution data in S180 tumor bearing mice are shown in Table 3; [18F]84 biodistribution data in S180 tumor-bearing mice are shown in Table 4; [18F]102 in S180 tumor-bearing mice, see Table 5; [18F]103 biodistribution data in S180 tumor-bearing mice are shown in Table 6.
TABLE 2 Compound [ 2 ]18F]75 distribution in S180 tumor-bearing mice (18-22g)a(LogP 0.2，IC503.7nM)
Figure BDA0002726826650000491
aThe data in the table are the mean ± standard deviation of three measurements;
table 3 Compound [ 2 ]18F]83 distribution in S180 tumor-bearing mice (18-22g)a(LogP 0.7，IC50108nM)
Figure BDA0002726826650000501
aThe data in the table are the mean ± standard deviation of three measurements;
TABLE 4 Compound [ 2 ]18F]84 in S180 tumor-bearing mice (18-22g)Cloth Conditiona(LogP 0.3，IC5036.2nM)
Figure BDA0002726826650000502
Figure BDA0002726826650000511
aThe data in the table are the mean ± standard deviation of three measurements;
as can be seen from tables 2 to 4, each of the F-18 labeled compounds of the present application was administered within 15 minutes after intravenous injection (Compound 218F]75) Or within 30 minutes (Compound 2 [ ]18F]83 the compound [ 2 ]18F]84) Significant enrichment occurs in tumors, with increasing levels in the tumor.
After intravenous injection, the distribution of each compound in each organ is generally in a descending trend due to decay of nuclide, but the content ratio of the drug in the tumor and in other organs is in an ascending trend, which shows that the content of the drug in the tumor is gradually increased compared with other organs, and also shows that the drug is relatively enriched in the tumor.
The results in tables 2-4 show that the radioactive marker of the invention has ideal biological distribution in S180 tumor-bearing mice, and also provides more sufficient experimental basis for the compounds to be developed into radioactive drugs for early diagnosis and research of tumors in the future.
Experimental example 3.F-18 radiopharmaceutical distribution in A549 tumor-bearing nude mice
A nude mouse A549 (human non-small cell lung cancer cell) bearing tumor (purchased from Beijing Wintolite, strain code 403, technical name Crl: NU-Foxn1NU) was injected tail vein with the compound [ prepared in example 7 ]18F]75 (10. mu. Ci in 0.1mL of physiological saline, 5% DMSO), at 30 minutes, mice were anesthetized with air containing 1.5% isoflurane (airflow rate about 1.5mL/min) and SuperArgus type small animal PET/CT (socieded) was used
Figure BDA0002726826650000512
A static scan was performed by de electromedicinna y Calidad, s.a.) (phase: 30min, collecting 10min), reconstructing the obtained data by using Sedeca Reconstruction software, deriving the image by using MMWKS SUPERARGUS software, and collecting the compound in the body of the mouse18F]The distribution results of 75 are shown in FIG. 6.
As can be seen from FIG. 6, the term [ 2 ]18F]75 have significant uptake in the tumor area (right dorsal side, arrow in FIG. 6) and can act as a tumor imaging agent. Further, the inventors found that [ 2 ]18F]75 also had significant uptake in the intestinal region (within the dashed rectangle in FIG. 6), and without being limited to any theory, the inventors believe that the compound [ 2 ]18F]75 may be metabolized primarily by the intestine and thus have a higher concentration in the intestine.
Experimental example 4[ alpha ], [ beta ], [ alpha ], [ beta18F]75 uptake blocking assay
To verify the FAK targeting effect of the compounds of the present application, VS-6063(CAS:1073160-26-5, Shanghai Shuen medicine) was used18F]75 uptake blocking assay.
The S180 tumor-bearing mice were divided into two groups, i.e., an inhibitory group and an uninhibited group, and the compound prepared in example 7 was injected into the tail vein18F]75 (10. mu. Ci in 0.1mL of physiological saline, 5% DMSO), wherein the mice in the inhibition group were injected one hour earlier with VS-6063(33mg/Kg) in the tail vein; injection compound [ 2 ]18F]After 75, the mice were sacrificed at 15 minutes and 30 minutes, respectively, and the compound [ 2 ] was detected by the method of Experimental example 218F]75 uptake in tumors, expressed as% ID/g, is shown in FIG. 7.
As can be seen in FIG. 7, the inhibitory group was the compound [ 2 ] for tumor at the 15 th and 30 th minutes18F]Intake of 75 was significantly reduced compared to uninhibited group (. about.P)<0.05, n ═ 6). VS-6063 has higher FAk targeting inhibition effect, and the compound is prepared after VS-6063 is injected into tail vein18F]75 is inhibited, indicating that the compound [ 2 ]18F]75 also have FAk targeting.
In summary, experimental example 1 shows that the compound of the present application has a certain inhibitory effect on FAK, and thus can be used for preparing a tumor treatment drug; experimental examples 2 and 3 show that the compound can be enriched in tumor, and Experimental example 4 shows that the compound has FAk targeting property, so that the compound can be enriched in tumor by targeting FAK, on one hand, the compound can be used for preparing tumor treatment medicines, and on the other hand, the compound can be used for preparing tumor diagnosis imaging agents.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.

Claims (10)

1. A FAK targeting compound having the structure shown in formula (i):
Figure FDA0002726826640000011
wherein R is selected from
Figure FDA0002726826640000012
Figure FDA0002726826640000013
R1Is selected from-NO2、
Figure FDA0002726826640000014
Figure FDA0002726826640000015
R2Selected from-OH,
Figure FDA0002726826640000021
2. The compound according to claim 1, selected from the following compounds:
Figure FDA0002726826640000022
Figure FDA0002726826640000031
Figure FDA0002726826640000041
3. a compound according to claim 1 or 2, when containing fluorine, wherein at least one fluorine is substituted18And F is substituted.
4. A compound according to claim 3, selected from the following compounds:
Figure FDA0002726826640000051
Figure FDA0002726826640000061
5. a process for preparing the compound of claim 1, comprising:
1) reacting a compound of formula (ii):
Figure FDA0002726826640000071
with a compound of general formula (III):
R’-NH2 (Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure FDA0002726826640000072
wherein R' is selected from
Figure FDA0002726826640000073
Figure FDA0002726826640000074
R’1Is selected from-NO2、
Figure FDA0002726826640000075
Figure FDA0002726826640000081
3) To be provided with
Figure FDA0002726826640000082
Substituted compounds
Figure FDA0002726826640000083
To obtain a compound of formula (V) or formula (VI):
Figure FDA0002726826640000084
4) to be provided with
Figure FDA0002726826640000085
Substituted compounds
Figure FDA0002726826640000086
Figure FDA0002726826640000087
Of (5) NO2Obtaining a compound of general formula (VII):
Figure FDA0002726826640000091
wherein R'2Selected from-OH,
Figure FDA0002726826640000092
5) reacting-NO in the compounds of the general formulae (IV) - (VII)2At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure FDA0002726826640000093
wherein R is as defined in claim 1;
when R is
Figure FDA0002726826640000094
When the compound is not substituted by fluorine-containing compounds;
when R is1Is composed of
Figure FDA0002726826640000095
The method also comprises the following reactions:
Figure FDA0002726826640000101
when R is2Is composed of
Figure FDA0002726826640000102
The method also comprises the following reactions:
Figure FDA0002726826640000103
6. the method of claim 5, wherein when at least one fluorine in R is substituted18When F is substituted, the fluorine-containing compound is18F labeled compound.
7. A precursor compound for preparing the compound of claim 1, selected from the group consisting of:
Figure FDA0002726826640000104
Figure FDA0002726826640000111
Figure FDA0002726826640000121
8. use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of tumours.
9. Use of a compound of claim 3 or 4 for the preparation of an imaging agent for tumor diagnosis.
10. A pharmaceutical composition comprising a compound of any one of claims 1-4.
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