CN112390760B - 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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CN112390760B
CN112390760B CN202011105540.8A CN202011105540A CN112390760B CN 112390760 B CN112390760 B CN 112390760B CN 202011105540 A CN202011105540 A CN 202011105540A CN 112390760 B CN112390760 B CN 112390760B
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fak
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tumor
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CN112390760A (en
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张华北
齐月恒
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Beijing Normal University
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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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; 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.
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 GDA0003611993310000021
wherein R is selected from
Figure GDA0003611993310000022
Figure GDA0003611993310000023
R 1 Is selected from-NO 2 、
Figure GDA0003611993310000024
Figure GDA0003611993310000025
R 2 Selected from-OH,
Figure GDA0003611993310000031
Figure GDA0003611993310000032
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 GDA0003611993310000033
with a compound of general formula (III):
R′-NH 2 (Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure GDA0003611993310000034
wherein R' is selected from
Figure GDA0003611993310000041
Figure GDA0003611993310000042
R′ 1 Is selected from-NO 2 、、
Figure GDA0003611993310000043
Figure GDA0003611993310000044
3) To be provided with
Figure GDA0003611993310000045
Substituted compounds
Figure GDA0003611993310000046
To obtain a compound of formula (V) or formula (VI):
Figure GDA0003611993310000051
4) to be provided with
Figure GDA0003611993310000052
Substituted compounds
Figure GDA0003611993310000053
Figure GDA0003611993310000054
Of (5) NO 2 Obtaining a compound of general formula (VII):
Figure GDA0003611993310000055
wherein R' 2 Selected from-OH,
Figure GDA0003611993310000061
5) reacting-NO in the compounds of the general formulae (IV) - (VII) 2 At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure GDA0003611993310000062
wherein R is as defined in claim 1;
when R is
Figure GDA0003611993310000063
When the compound is not substituted by fluorine-containing compounds;
when R is 1 Is composed of
Figure GDA0003611993310000064
The method also comprises the following reactions:
Figure GDA0003611993310000065
when R is 2 Is composed of
Figure GDA0003611993310000066
The method also comprises the following reaction:
Figure GDA0003611993310000071
in a third aspect, the present application provides a precursor compound for the preparation of a compound provided in the first aspect of the present application, selected from the following compounds:
Figure GDA0003611993310000072
Figure GDA0003611993310000081
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 [ 2 ] 18 F]HPLC co-injection analysis chromatogram of 75 with its F-19 standard compound 75.
FIG. 2 is F-18 radioligand [ alpha ], [ beta ] -a 18 F]An HPLC co-injection analysis chromatogram of 83 with its F-19 standard compound 83.
FIG. 3 is F-18 radioligand [ alpha ], [ beta ] -cyclodextrin 18 F]HPLC co-injection analysis chromatogram of 84 with its F-19 standard compound 84.
FIG. 4 is F-18 radioligand [ 2 ] 18 F]102 and its F-19 standard compound 102.
FIG. 5 is F-18 radioligand [ 2 ] 18 F]103 and its F-19 standard compound 103.
FIG. 6 is the compound [ 2 ] in a mouse body 18 F]75, and the result is a distribution.
FIG. 7 is the compound [ 2 ] 18 F]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 GDA0003611993310000101
wherein R is selected from
Figure GDA0003611993310000102
Figure GDA0003611993310000103
R 1 Is selected from-NO 2 、、
Figure GDA0003611993310000111
Figure GDA0003611993310000112
R 2 Selected from-OH,
Figure GDA0003611993310000113
In some preferred embodiments of the present application, the FAK-targeting compound has a structure represented by general formula (i):
Figure GDA0003611993310000114
wherein R is selected from
Figure GDA0003611993310000115
Figure GDA0003611993310000121
Wherein the content of the first and second substances,
when R is 2 When it is-OH, R 1 Is selected from-NO 2 、
Figure GDA0003611993310000122
Figure GDA0003611993310000123
When R is 2 Is composed of
Figure GDA0003611993310000124
When R is 1 Is selected from-NO 2 、
Figure GDA0003611993310000125
Figure GDA0003611993310000126
When R is 2 Is selected from
Figure GDA0003611993310000127
When the current is over; r 1 is-NO 2 ；
When R is 2 Is composed of
Figure GDA0003611993310000131
When R is 1 Is selected from
Figure GDA0003611993310000132
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 GDA0003611993310000133
Figure GDA0003611993310000141
Figure GDA0003611993310000151
in some embodiments of the first aspect of the present applicationWherein when said compound contains fluorine, at least one fluorine is substituted 18 And F is substituted.
In some embodiments of the first aspect of the present application, at least one fluorine is substituted with a fluorine atom 18 The F-substituted compound is selected from the following compounds:
Figure GDA0003611993310000161
Figure GDA0003611993310000171
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 GDA0003611993310000181
with a compound of general formula (III):
R′-NH 2 (Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure GDA0003611993310000182
wherein R' is selected from
Figure GDA0003611993310000183
Figure GDA0003611993310000184
R′ 1 Is selected from-NO 2 、
Figure GDA0003611993310000191
Figure GDA0003611993310000192
3) To be provided with
Figure GDA0003611993310000193
Substituted compounds
Figure GDA0003611993310000194
To obtain a compound of formula (V) or formula (VI):
Figure GDA0003611993310000195
4) to be provided with
Figure GDA0003611993310000196
Substituted compounds
Figure GDA0003611993310000197
Figure GDA0003611993310000201
Of (5) NO 2 Obtaining a compound of general formula (VII):
Figure GDA0003611993310000202
wherein R' 2 Selected from-OH,
Figure GDA0003611993310000203
5) reacting-NO in the compounds of the general formulae (IV) - (VII) 2 At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure GDA0003611993310000204
wherein R is as defined in claim 1;
when R is
Figure GDA0003611993310000205
When the compound is not substituted by fluorine-containing compounds;
when R is 1 Is composed of
Figure GDA0003611993310000211
The method also comprises the following reactions:
Figure GDA0003611993310000212
when R is 2 Is composed of
Figure GDA0003611993310000213
The method also comprises the following reactions:
Figure GDA0003611993310000214
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 GDA0003611993310000215
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 GDA0003611993310000221
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 H 2 Obtained 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 compound 2 At least one of-OH or-OTs, the fluorine-containing compound may be selected from:
Figure GDA0003611993310000222
or alkali metal fluorides, in which case, as a rule
Figure GDA0003611993310000223
React with-OH in the precursor compound to
Figure GDA0003611993310000224
To be provided with
Figure GDA0003611993310000225
and-NO 2 reduced-NH 2 React to form
Figure GDA0003611993310000226
-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 fluorine 18 When F is substituted, it is possible to use 18 F-labelled compound with said precursor compound, preferably said compound 18 The F-labelled compound may be selected from
Figure GDA0003611993310000231
Or K 18 F; accordingly, it is common to
Figure GDA0003611993310000232
React with-OH in the precursor compound to
Figure GDA0003611993310000233
To be provided with
Figure GDA0003611993310000234
and-NO 2 reduced-NH 2 React to form
Figure GDA0003611993310000235
With K 18 F obtained by reaction with-OTs 18 F。
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 compound 18 F labeled fluorine-containing compound, namely the FAK targeted compound of the application can be obtained, or 18 The 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 GDA0003611993310000236
Figure GDA0003611993310000241
Figure GDA0003611993310000251
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 provides 18 The 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 method 18 The F-labeled compound targeting FAK can be specifically combined with FAK, so that the F-labeled compound can be enriched and combined in tumors 18 F 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 adenocarcinoma of the ovary, endometrioid adenocarcinoma of the ovary, and serous adenocarcinoma of the ovary. 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 GDA0003611993310000261
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);
1 H NMR(400MHz,CDCl 3 ,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);
1 H 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).
13 C 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);
1 H 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),.
13 C 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%);
1 H 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).
13 C 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 C 20 H 19 BrN 7 O 5 +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);
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 22 H 22 BrFN 7 O 5 + 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 GDA0003611993310000291
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);
1 H NMR(600MHz,DMSO-d 6 ,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 C 34 H 37 BrN 7 O 10 S + 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);
1 H NMR(600MHz,CD 3 OD,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 C 27 H 30 BrFN 7 O 7 + 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);
1 H NMR(600MHz,CD 3 OD,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 C 24 H 26 BrFN 7 O 7 + 622.1056,found 622.1060[M+H] +
Preparation example 3 organic Synthesis of Compound 75
The synthetic route is as follows:
Figure GDA0003611993310000311
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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 11 H 14 N 3 O 5 + 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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 11 H 15 N 3 NaO 3 + 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);
1 H NMR(600MHz,DMSO-d 6 ,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 C 25 H 28 BrN 8 O 5 + 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);
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 27 H 31 BrFN 8 O 5 + 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 GDA0003611993310000331
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);
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 11 H 14 N 3 O 5 + 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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 11 H 15 N 3 NaO 3 + 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 the reaction was completed, the reaction solution 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);
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(600MHz,DMSO-d 6 ,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 C 25 H 28 BrN 8 O 5 + 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);
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 C 27 H 31 BrFN 8 O 5 + 645.1579,found 645.1581[M+H] + .
preparation example 5 organic Synthesis of Compound 95
The synthetic route is as follows:
Figure GDA0003611993310000361
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%).
1 H NMR(400MHz,CDCl 3 ,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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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 GDA0003611993310000371
Figure GDA0003611993310000381
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%);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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);
1 H NMR(400MHz,DMSO-d 6 ,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).
13 C NMR(100MHz,DMSO-d 6 ,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;
1 H NMR(600MHz,DMSO-d 6 ,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).
13 C NMR(600MHz,DMSO-d 6 ,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);
1 H NMR(600MHz,CD 3 OD,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).
13 C NMR(600MHz,CD 3 OD,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 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 give compound 103(68.8mg, white solid, 76.1% yield);
1 H NMR(600MHz,CD 3 OD,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 C 35 H 37 BrFN 10 O 8 + 823.1958,found 823.1953[M+H] + .
preparation example 7 Compound [ 2 ] 18 F]75、[ 18 F]83 and [ 2 ] 18 F]84F-18 labeling and isolation purification
[ 18 F]Synthesis of FETos:
Figure GDA0003611993310000411
15mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 1mg of K 2 CO 3 Dissolved in 0.3mL of water, mixed and captured on a QMA column 18 F - Leaching into a reaction flask, and adding N at 100 DEG C 2 Blowing 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 GDA0003611993310000413
10X 250 mm). Product 2-, [ 2 ] 18 F]Fluoroethyl tosylate [ 2 ] (] 18 F]FETos) was 12 minutes.
[ 18 F]75, synthesis:
Figure GDA0003611993310000412
2-, [ product of the previous step ] 18 F]Fluoroethyl tosylate (, () 18 F]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, N 2 The 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 GDA0003611993310000422
10X 250mm) liquid phase separation of the product. As shown in FIG. 1, the compound [ 2 ] 18 F]The retention time of the 75 liquid phase was 22.8 minutes, and the radioactive compound was confirmed by the analysis of co-injection with the compound 75 liquid phase 18 F]75 accuracy.
[ 18 F]83、[ 18 F]84, synthesis:
Figure GDA0003611993310000421
[ 18 F]83 Synthesis:
15mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 1mg of K 2 CO 3 Dissolving in 0.3mL water, and mixing to obtain 1.0mL Kryptofix 222/K 2 CO 3 An eluent; capturing on QMA column with the eluate 18 F - Rinsing into a reaction flask, and adding N at 100 DEG C 2 Blowing 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 labelled precursor 82(4mg) in anhydrous DMF (0.3mL) was flash-washedQuickly adding into the reaction bottle, sealing, and reacting at 110 deg.C for 20 min. After the reaction was complete, a C18 reversed phase semi-preparative column (Agela Technologies, 5 μm,
Figure GDA0003611993310000425
10X 250mm) to obtain a radiolabeled compound 18 F]83。
[ 18 F]84, synthesis:
compound [ 2 ] grafted to a Radio-HPLC liquid phase 18 F]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 GDA0003611993310000424
10X 250mm) to obtain a radiolabeled compound 18 F]84。
As shown in FIG. 2, the compound [ 2 ] 18 F]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 ] 18 F]83 accuracy.
As shown in FIG. 3, the compound [ 2 ] 18 F]84 has a liquid phase retention time of 3.4 minutes, and the liquid phase coinjection analysis with the compound 84 confirms the radioligand [ 2 ] 18 F]84, accuracy.
Preparation example 8 Compound [ 2 ] 18 F]102 and [ 2 ] 18 F]103F-18 labelling and isolation purification
The synthetic route is as follows:
Figure GDA0003611993310000431
Figure GDA0003611993310000441
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%).
1 H NMR(400MHz,CDCl 3 ,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 x 2). The precipitate was compound 89, which did not require further purification and did not interfere with 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%).
1 H NMR(400MHz,CD 3 OD,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).
19 F NMR(400MHz,CD 3 OD,δppm):-80.06(s,3F),-140.90(m,4F).
First 2mg of Kryptofix 222 was dissolved in 0.7mL of anhydrous acetonitrile, 2mg of KHCO 3 Dissolving in 0.3mL water, and mixing to obtain 1.0mL Kryptofix 222/K 2 CO 3 An eluent; capturing on QMA column with the eluate 18 F - Leaching into a reaction flask, and adding N at 100 DEG C 2 Blowing 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 to dilute the solutionReleasing, drawing into a syringe, injecting into a sterile penicillin vial by MCX Plus Sep-Pak, N at 60 ℃ 2 Blow-drying with air, i.e., pure radiolabeled compound [ alpha ], [ beta ] -cyclodextrin 18 F]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 ], [ 18 F]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 compound 18 F]102。
The compound 2 grafted from Radio-HPLC 18 F]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 ] 18 F]103。
As shown in FIG. 4, the compound [ 2 ] 18 F]102 has a liquid phase retention time of 5.5 minutes, and a liquid phase coinjection analysis with the compound 102 confirms the radioligand [ 2 ] 18 F]102, accuracy of the measurement.
As shown in FIG. 5, the compound [ 2 ] 18 F]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 ] 18 F]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 GDA0003611993310000462
Method) for activity detection. FAK kinase was purchased from cana corporation; detection kitPurchased from Cisbio; 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 60 min 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 5 50 The value is obtained.
TABLE 1 results of in vitro inhibition of FAK enzyme Activity by Compounds
Figure GDA0003611993310000461
Figure GDA0003611993310000471
Figure GDA0003611993310000481
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 102 50 The 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 establishment of animal models
Under aseptic condition, disinfecting oxter skin of normal female Kunming mouse (18-22g) with 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) × 10 7 0.1mL of the cells per mL was inoculated subcutaneously into the axilla 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 HPLC 18 F]75、[ 18 F]83 and [ 2 ] 18 F]84(10 μ Ci, dissolved in 0.1mL of physiological saline containing 5% DMSO) was injected into S180 tumor-bearing mice by tail vein injection (18-22g, female, n ═ 5), the mice were sacrificed at 5min, 15min, 30min, 60min, 120min, and the bleeding, brain, heart, liver, spleen, lung, kidney, muscle, bone, intestine, stomach, S180 tumor and tail were dissected, the wet weight of each organ was measured and counted using γ -counter, the uptake per tissue was finally expressed as% ID/g%.
2.3 discussion of results
[ 18 F]75 biodistribution data in S180 tumor-bearing mice are shown in Table 2; [ 18 F]83 biodistribution data in S180 tumor bearing mice are shown in Table 3; [ 18 F]The biodistribution data of 84 in S180 tumor-bearing mice are shown in Table 4.
TABLE 2 Compound [ 2 ] 18 F]75 distribution in S180 tumor-bearing mice (18-22g) a (LogP 0.2，IC 50 3.7nM)
Figure GDA0003611993310000491
a The data in the table are the mean ± standard deviation of three measurements;
table 3 Compound [ 2 ] 18 F]83 distribution in S180 tumor-bearing mice (18-22g) a (LogP 0.7，IC 50 108nM)
Figure GDA0003611993310000492
Figure GDA0003611993310000501
a The data in the table are the mean ± standard deviation of three measurements;
TABLE 4 Compound [ 2 ] 18 F]Distribution of 84 in S180 tumor-bearing mice (18-22g) a (LogP 0.3，IC 50 36.2nM)
Figure GDA0003611993310000502
Figure GDA0003611993310000511
a The 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 2 18 F]75) Or within 30 minutes (Compound 2 [ ] 18 F]83 the compound [ 2 ] 18 F]84) Significant enrichment occurred in tumors, in whichThe content is gradually increased.
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 ] 18 F]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 GDA0003611993310000512
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 mouse 18 F]The distribution results of 75 are shown in FIG. 6.
As can be seen from FIG. 6, the term [ 2 ] 18 F]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 ] 18 F]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 ] 18 F]75 may be metabolized primarily by the intestine and thus have a higher concentration in the intestine.
Experimental example 4[ alpha ], [ beta ], [ alpha ], [ beta ] -state 18 F]75Uptake 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 used 18 F]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 vein 18 F]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 ] 18 F]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 2 18 F]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 minutes 18 F]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 vein 18 F]75 is inhibited, indicating that the compound [ 2 ] 18 F]75 also has FAk targeting.
In summary, the 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 therapeutic 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 FDA0003644891400000011
wherein R is selected from
Figure FDA0003644891400000012
R 1 Is selected from-NO 2 、
Figure FDA0003644891400000013
Figure FDA0003644891400000014
R 2 Selected from-OH,
Figure FDA0003644891400000015
2. The compound according to claim 1, selected from the following compounds:
Figure FDA0003644891400000016
Figure FDA0003644891400000021
3. a compound according to claim 1 or 2, when containing fluorine, wherein at least one fluorine is substituted 18 And F is substituted.
4. A compound according to claim 3, selected from the following compounds:
Figure FDA0003644891400000031
5. a process for preparing the compound of claim 1, comprising:
1) reacting a compound of formula (II):
Figure FDA0003644891400000041
with a compound of general formula (III):
R’-NH 2 (Ⅲ)，
the compound of the general formula (IV) is synthesized by p-toluenesulfonic acid in an organic solvent at 90-110 ℃:
Figure FDA0003644891400000042
wherein R' is selected from
Figure FDA0003644891400000043
R’ 1 Is selected from-NO 2 、
Figure FDA0003644891400000044
3) To be provided with
Figure FDA0003644891400000045
Substituted compounds
Figure FDA0003644891400000046
To obtain a compound of formula (V) or formula (VI):
Figure FDA0003644891400000051
4) to be provided with
Figure FDA0003644891400000052
Substituted compounds
Figure FDA0003644891400000053
Figure FDA0003644891400000054
Of (5) NO 2 Obtaining a compound of general formula (VII):
Figure FDA0003644891400000055
wherein R' 2 Selected from-OH,
Figure FDA0003644891400000056
5) reacting-NO in the compounds of the general formulae (IV) - (VII) 2 At least one of-OH or-OTs, substituted with a fluorine-containing compound to obtain a compound of formula (I):
Figure FDA0003644891400000061
wherein R is as defined in claim 1;
when R is
Figure FDA0003644891400000062
When the compound is not substituted by fluorine-containing compounds;
when R is 1 Is composed of
Figure FDA0003644891400000063
The method also comprises the following reactions:
Figure FDA0003644891400000064
when R is 2 Is composed of
Figure FDA0003644891400000065
The method also comprises the following reactions:
Figure FDA0003644891400000071
6. the method of claim 5, wherein when at least one fluorine in R is substituted 18 When F is substituted, the fluorine-containing compound is 18 F labeled compound.
7. A precursor compound for preparing the compound of claim 1, selected from the group consisting of:
Figure FDA0003644891400000072
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 according to claim 3 or 4 for the preparation of an imaging agent for the diagnosis of tumors.
10. A pharmaceutical composition comprising a compound of any one of claims 1-4.
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