CN114716385B - Compound of targeted focal adhesion kinase, preparation method and application - Google Patents

Compound of targeted focal adhesion kinase, preparation method and application Download PDF

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CN114716385B
CN114716385B CN202210367278.7A CN202210367278A CN114716385B CN 114716385 B CN114716385 B CN 114716385B CN 202210367278 A CN202210367278 A CN 202210367278A CN 114716385 B CN114716385 B CN 114716385B
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CN114716385A (en
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张华北
李晔
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Beijing Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0463—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • 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

Abstract

The invention relates to a compound of targeted focal adhesion kinase, a preparation method and application thereof. The focal adhesion kinase targeting compounds of the present invention have the general formula:the focal adhesion kinase targeting compound of the present invention has a simple structure and can be used as a labeling precursor, preferably as a radiolabeled precursor. The compound for targeting focal adhesion kinase also has application in the targeted focal adhesion kinase, application in preparing tumor therapeutic drugs or application in preparing tumor diagnostic imaging agents, and has good application effect.

Description

Compound of targeted focal adhesion kinase, preparation method and application
Technical Field
The invention relates to the technical field of medicines, in particular to a compound for targeting focal adhesion kinase, a preparation method and application thereof.
Technical Field
Focal adhesion kinase (Focal adhesion kinase, fak) plays a key role in tumor invasion and metastasis, is a cytoplasmic tyrosine kinase, participates in multiple functions of cells, plays an important role in tumor cell invasion, metastasis, angiogenesis, signal transduction and the like, is overexpressed in various tumor cells and is related to the malignancy of the tumor cells, so that the focal adhesion kinase can be a molecular marker for tumor diagnosis, fak is positioned at a signal transduction intersection point of integrin and receptor tyrosine kinase, can transmit signals of extracellular matrixes into cells, and can effectively block some signal paths related to tumors by inhibiting the functions of the Fak. Overexpression of FAK may be associated with its gene amplification and has also been shown to play an important role in cell survival, migration and invasion. Therefore, FAK becomes an important target for tumor diagnosis and treatment.
Disclosure of Invention
Aiming at the technical limitations, the invention provides a compound for targeting focal adhesion kinase, a preparation method and application thereof. The compound of the invention has simple structure and better action effect.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
it is an object of the present invention to provide a focal adhesion kinase targeting compound having the structural formula of formula I:
R 1 selected from the group consisting of
R 2 Selected from hydrogen or
The R is 3 Selected from alkoxy, alkoxy substituted by alkyl,A hydroxyl group;
the R is 1 、R 2 Or R is 3 R in (a) 7 The same or different are each independently selected from C1-C5 alkyl groups;
the R is 4 Selected from hydrogen, alkoxy, nitro,
The R is 8 A linear alkyl or cycloalkyl group selected from C1-C5; the R is 9 Or R is 10 The same or different, each independently selected from methyl, heteroaryl containing halogen substituents; the X is selected from halogen;
the R is 5 Selected from halogen or alkyl substituted by halogen.
Preferably, among the focal adhesion kinase-targeting compounds,
the R is 1 、R 2 Or R is 3 R in (a) 7 The same or different are each independently selected from C1-C2 alkyl groups; and/or the number of the groups of groups,
the R is 3 Or R is 4 The alkyl in the alkoxy is selected from C1-C2 alkyl;
The R is 3 In (2), alkyl-substituted alkoxy has the general formula:the R is 11 Selected from halogen, hydroxy, OTs groups; said n is selected from 1-5;
the R is 8 Selected from C1-C3 alkyl or C3-C5 cycloalkyl;
the R is 9 、R 10 Independently and separatelySelected from F-containing substituted pyrazolyl or pyridinyl.
Preferably, the method comprises the steps of,
the R is 1 、R 2 Or R is 3 R in (a) 7 Are all selected from methyl groups;
the R is 3 Or R is 4 The alkyl in the alkoxy is selected from methyl;
the R is 5 Selected from bromine or CF 3 ；
The R is 11 Selected from F or 18 F, performing the process; said n is selected from 1-3;
the R is 8 Selected from ethyl or cyclopropane groups;
the R is 9 、R 10 Independently selected from
Preferably, the focal adhesion kinase-targeting compound has the following structural formula:
and n is selected from 1-3.
Preferably, the method comprises the steps of,
the R is 4 Selected from hydrogen, preferably said R 2 Also selected from hydrogen.
Preferably, the focal adhesion kinase-targeting compound comprises at least one of the following compounds:
another object of the present invention is to provide a method for producing a focal adhesion kinase-targeting compound according to one of the objects of the present invention, comprising the steps of:
(1)wherein the hydroxy group is R 3 Group substitution; the R is 3 Selected from alkoxy, alkoxy substituted by alkyl, < ->Optionally hydroxy;
(2) Optionally, the composition may be used in combination with,the nitro group in (2) being further bound by R 4 Group substitution; the R is 4 Selecting Nitro quilt R 4 The group substitution process includes a process in which a nitro group is reduced to an amino group and then amino hydrogen is substituted;
the second method is as follows:with the general formula R' -NH 2 The compounds shown are reacted to synthesize the compound of the general formula (IV) by the catalysis of p-toluenesulfonic acid>Wherein R' is selected from->R’ 1 Selected from R 3 A group or a nitro group.
The preparation method of the focal adhesion kinase targeting compound can be prepared according to the conventional preparation method, and also can be prepared by adopting the method provided by the invention, and specifically comprises the following steps: the synthetic route for the preparation of the compounds of the formula (I-I) is generally as follows (two methods in total, designated as method A and method B):
method A:
the specific preparation method of the method A comprises the following steps:
a1 5-bromo-2, 4-dichloropyrimidine, 2-amino-N-methylbenzamide, and potassium carbonate were dissolved in DMF, and the system was allowed to react at 70℃for 15 hours to give compound 1.
A2 Compound 1 (1 eq), p-methoxyaniline (1.2 eq), p-toluenesulfonic acid monohydrate (0.4 eq) were dissolved in 1.4-dioxane, and the reaction system was stirred at 70 ℃ overnight to give compound 2.
A3 Demethoxy compound 2 under boron tribromide and methylene chloride conditions to give compound 3.
A4 Compound 3 and compounds 9a-9c are reacted with each other in potassium carbonate and DMF at 70 ℃ to obtain compounds 4a-4c.
A5 The compounds 4a-4c are reacted under stirring of p-toluenesulfonyl chloride, triethylamine and methylene dichloride at room temperature to obtain the compounds 5a-5c.
A6 Compounds 6a-6c were obtained by heating compounds 5a-5c to 50℃under TBAF and tetrahydrofuran.
The specific preparation method of the method B comprises the following steps:
a1 Reacting the compound 4-aminophenol with the compounds 9a-9c in potassium carbonate and DMF at 70 ℃ to obtain the compounds 7a-7c.
A2 The compounds 7a-7c are stirred at room temperature under the condition of hydrogen and palladium carbon to obtain the compounds 8a-8c.
A3 The preparation of the target compound is consistent with the method of the step A4), and is different from the method of the step A4, and the specific method is as follows: compounds 8a-8c and 1 were heated to 70℃under p-toluenesulfonic acid monohydrate and 1, 4-dioxane to give compounds 4a-4c.
A4 Compound 1 and 4-aminophenylether were heated to 70℃under p-toluenesulfonic acid monohydrate and 1, 4-dioxane to give compound LY-4.
In the preparation of the compounds of the formulae (I-II), the synthetic route according to the invention is as follows, designated as method C:
/>
the specific preparation method of the method C comprises the following steps:
B1 5-bromo-2, 4-dichloropyrimidine was dissolved in THF, aqueous ammonia was slowly added dropwise, and stirred at room temperature for two hours to give compound 10.
B2 Dissolving the compound 10 and potassium carbonate in DMF, then slowly adding dinitrofluorobenzo, and reacting at 70 ℃ for 5-7 hours to obtain the compound 11.
B3 Compound 11 was reduced to amino group under the condition of iron powder ammonium chloride to obtain compound 12.
B4 Compound 12 and acetyl chloride are stirred for half an hour in an ice bath by using triethylamine as alkali and anhydrous dichloromethane as a solvent to obtain compound 13.
B5 Compound 13, 4-methoxy-3-nitroaniline is reacted with p-toluenesulfonic acid monohydrate and 1, 4-dioxane at 70 ℃ to obtain compound 14.
B6 Compound 15 synthesis method is the same as step B3.
B7 Compound 15, N-acetyl-beta-alanine and HATU, DIPEA, DMF are stirred at room temperature to obtain compound 16.
B8 Compound 17 synthesis method is the same as step A3.
B9 The synthesis of compounds 18a-18c, 20 is the same as step A4 of method one.
B10 The synthesis of compounds 19a-19c, 21 is carried out in the same way as step A6 of method one.
B11 Compound 22a, 22B, 24a and 24B were synthesized in the same manner as in step B7.
B12 Step A4 of the same method as the synthesis method of the compounds 23a and 23 b.
B13 Compound 26 synthesis method and method A1 of method one.
B14 Compound 27 was synthesized in the same manner as in step B3.
B15 Compound 28 synthesis method is the same as step B7.
B16 Step A1 of the same method as the synthesis method of the compound 29.
B17 Compound diol is stirred at room temperature by taking TBSCl, imidazole and methylene dichloride as solvents to obtain the compounds 30a-30c.
B18 Step A5 of the same method as the synthesis of the compounds 31a to 31 c.
B19 Compound 32 synthesis method is the same as step B7.
B20 Method for synthesizing Compounds 33a-33c
B21 Dissolving the compounds 33a-33c with tetrahydrofuran, adding potassium tert-butoxide, adding methyl iodide after 30 minutes, and stirring for 1 hour to obtain the compounds 34a-34c.
B22 Step A2 of the same method as the synthesis method of the compounds 35a-35 c.
B23 Step A4 of the same method as the synthesis method of the compounds 36a-36 c.
B24 Dissolving the compounds 36a-36c in ethyl acetate, adding an ethyl acetate solution of hydrochloric acid, and stirring at room temperature overnight to obtain the compounds 37a-37c.
B25 Compound 38a-38c, as in step A5 of method one.
B26 Compound 39a-39c is synthesized in the same manner as in step A6 of the first method.
B27 Compound 40 synthesis method as in step A4 of method one.
B28 Compound 41 synthesis method as in step A1 or B3 of method two.
B29 Compound 41 and 2, 4-dichloro-5-trifluoromethyl pyrimidine under the condition of zinc chloride to obtain compound 42
B30 Compound 43 is synthesized in the same manner as in step A1 of the first method.
B31 Compound 44 synthesis method with steps B3 and B4, two steps.
Synthetic routes to compounds LY-47 through LY-52:
raw materials and reaction conditions (a) K 2 CO 3 ,DMF,70℃；(b)H 2 ,10％Pd/C,MeOH,50℃；(c)K 2 CO 3 ,THF,60℃；(d)1)SOCl 2 ,DCM,reflux；2)THF,0℃；(e)Fe powder:NH 4 Cl＝1:1(n:n),MeOH:THF:H 2 O＝5:5:2(v:v:v).
Raw materials and reaction conditions (a) isopanol, p-Toluenesulfonic acid monohydrate,90 ℃; (b) TsCl, et 3 N,anhydrous DCM,RT；(c)K 222 ,KF,K 2 CO 3 ,DMF.
In the invention, the addition amount of each substance in the preparation method of the focal adhesion kinase targeting compound is not particularly required, and the synthesis method is selected from the above disclosed synthesis methods according to the conventional dosage of similar reactions in the field or by adjustment of conventional means, and can also be a synthesis method of similar structures or similar functional group transformation disclosed in the field.
It is a further object of the present invention to provide the use of a compound according to one of the objects of the present invention as a labelling precursor, preferably as a radiolabelled precursor.
It is still another object of the present invention to provide an application of the compound of one of the objects of the present invention in targeting focal adhesion kinase, or in preparing a tumor therapeutic drug, or in treating a tumor with a combination drug, or in preparing a tumor diagnostic imaging agent, preferably the tumor is selected from lung cancer, liver cancer, ovarian cancer, pancreatic cancer, colon cancer, prostate cancer, and glioma.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of one of the objects of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical compositions can be formulated for particular routes of administration, such as oral, parenteral, rectal, and the like. Oral formulations such as tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, relaxants, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups and emulsions; sublingual administration; is taken orally; parenteral, e.g., by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as a sterile injectable aqueous or nonaqueous solution or suspension); transnasal, including administration to the nasal mucosa, e.g., by inhalation spray; topical, for example in the form of a cream, ointment or salve, or rectally, for example in the form of suppositories. They may be administered alone, but will typically be administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.
Compared with the prior art, the invention has at least the following advantages:
1) The invention designs and synthesizes a series of target FAK compounds, which can be used as small molecular compounds for inhibiting tumor growth and also can be used as small molecular compounds for inhibiting rare diseases;
2) The compound can be used for marking radionuclide F-18, is used for diagnosing tumors, and can be used as a tumor imaging agent;
3) The invention provides a method for marking a target FAK small molecular compound by a one-step method during the preparation of related radioactive medicines, which has high marking rate, and most of the compounds in the patent applied by the research team in the prior art are marked by a two-step method, so that the marking rate is very low.
4) The invention makes a large amount of FAK inhibitors, and discovers R through kinase activity test 4 、R 2 The kinase inhibition activity is generally higher when the compound is hydrogen, and the compound is better combined with a protein cavity from the analysis of a theoretical model.
5) The FAK inhibitor has good activity, taking the compound LY-3 as an example, the kinase inhibition activity of the FAK inhibitor is higher than that of the current clinical secondary FAK drug VS-6063, and the tumor inhibition effect of the compound LY-3 is found to be better than that of the VS-6063 and the current marketed lung cancer drug erlotinib through tumor inhibition experiments, so that the single administration effect of the compound LY-3 is good.
6) The FAK inhibitor can be combined, has better tumor inhibiting effect than single administration in the aspect of combined administration, and the combined erlotinib of the compound LY-21 is taken as an example to show better tumor inhibiting effect than single administration in a lung cancer mouse model, and the activity degree of the mouse is also good and the weight of the mouse is not reduced. The toxicity is small. The effect that 1+1 is more than 2 can be achieved. Therefore, the combination drug has very important significance.
7) The FAK inhibitor of the invention can be radiolabeled by a one-step method, and has high labeling rate. And the tumor has high uptake and clear imaging, and has very important significance in tumor diagnosis.
Drawings
FIG. 1 is a diagram of LY-21 and a tumor inhibition experiment of a prior compound;
FIG. 2 is a mass graph of LY-21 and prior art compounds taken 28 days after tumor removal and weighing;
FIG. 3 is a graph of an experimental view of LY-3 and the tumor inhibition of a prior compound;
FIG. 4 is a mass graph of LY-3 and prior art compounds taken 28 days after tumor removal and weighing;
FIG. 5 is a graph showing the effect of LY-10 on radiodiagnosis.
Reference numerals: 1-tumor site
Detailed Description
The present invention will be described in further detail below in order to make the objects, technical solutions and advantages of the present invention more apparent. It is to be understood that the description is only intended to illustrate the invention and is not intended to limit the scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and the terms used herein in this description of the invention are for the purpose of describing particular embodiments only and are not intended to be limiting of the invention. Reagents and instruments used herein are commercially available, and reference to characterization means is made to the relevant description of the prior art and will not be repeated herein.
For a further understanding of the present invention, the present invention will be described in further detail with reference to the following preferred embodiments.
Example 1
Synthesis of Compound 10 by the Synthesis procedure illustrated in method C
5-bromo-2, 4-dichloropyrimidine (30 g,131.65 mmol) was dissolved in THF (150 mL), aqueous ammonia (150 mL) was slowly added dropwise, stirred at room temperature for two hours, the reaction was complete by TLC detection, 150mL of water was added, extracted with EA (100 mL x 3), the organic phase dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 24.7g of a white solid product, yield: 90%.1H NMR (600 MHz, DMSO-D6) δ8.18 (D, J=43.5 Hz, 2H), 7.31 (s, 1H).
Synthesis of Compound 11
Compound 10 (20 g,95.95 mmol), potassium carbonate (15.91 g,115.14 mmol) were added to a reaction flask, DMF (150 mL) was added, stirred at room temperature for 15 minutes, then dinitrofluorobenzene (21.4 g,115.14 mmol) was slowly added, the reaction system was heated to 70 ℃ and after five hours the reaction was checked to be complete by TLC, the reaction system was warmed to room temperature, 20mL of water was added, a yellow solid was precipitated, filtered, the filter cake was washed with water, the filter cake was collected, recrystallized from ethyl acetate petroleum ether to give 31.19g of a yellow solid product, yield: 86.8%.1H NMR (400 MHz, DMSO-D6) δ10.58 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.63 (D, J=10.2 Hz, 1H), 8.41 (D, J=9.7 Hz, 1H) 13C NMR (151 MHz, DMSO-D6) δ 160.66,157.77,143.00,140.10,138.46,129.49,126.17,122.03,106.04.MS(ESI+):m/z calcd for C 10 H 5 BrClN 5 O 4 ,372.9213；found,373.9293(M+H+)
Synthesis of Compound 13
Compound 11 (20 g,53.4 mmol) was dissolved in tetrahydrofuran (150 mL), methanol (150 mL), water (50 mL), iron powder (7.45 g,133.5 mmol), ammonium chloride (7.14 g,133.5 mmol) was added, stirred at 70℃for 6 hours, the reaction was complete by TLC detection, filtered, the filtrate was concentrated, then dissolved in tetrahydrofuran (150 mL) and placed in an ice-water bath, triethylamine (13.5 g,133.5 mmol) was added, stirred in an ice-water bath for 40 minutes, then acetyl chloride (9.22 g,117.48 mmol) was slowly added dropwise after 1 hour, quenched by slow addition of water (150 mL), extracted with ethyl acetate, the organic phase was collected, dried with anhydrous magnesium sulfate, the organic phase was concentrated, and column chromatography (PE: EA=5:1 to 1:1) gave 7.66g of white solid in two steps of yield: 36%.
Synthesis of Compound 25
Compound 13 (3 g,7.56 mmol), p-toluenesulfonic acid (520 mg,3.02 mmol), 4-amino-2-nitrophenol (1.75 g,11.34 mmol) were added to a 250mL round bottom flask, 1, 4-dioxane (100 mL) was added to dissolve the starting material, replace argon, then the reaction system was stirred at 70 ℃ for 24 hours, the reaction was complete by TLC detection, the reaction system was quenched to room temperature by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, concentrated, recrystallized to give 3.11g of a yellow solid product, yield: 79.6%.
Example 2
Synthesis of Compound 26
2-bromo-N, N-dimethylacetamide (2 g,12.05 mmol), potassium carbonate (2 g,14.46 mmol) and potassium iodide (200.9 mg,1.21 mmol) were added to a 100mL round bottom flask and dissolved in DMF (50 mL), compound 25 (6.22 g,12.05 mmol) was slowly added dropwise to the reaction system, and the mixture was left to react at 50℃for 4 hours after the dropwise addition, and the reaction was completed by TLC, and the reaction was allowed to proceed to room temperature, and 100mL of water was added to precipitate a yellow solid, filtered, and the filter cake was washed with water and dried to give 5.8g of the product, yield: 80%.
Example 3
Synthesis of Compound LY-23
Compound 26 (100 mg,0.17 mmol), potassium carbonate (35.93 mg,0.26 mmol), sodium iodide (2.5 mg,0.017 mmol) were added to a 10mL round bottom flask, 1mL of ldmf was added, a solution of 2-fluoroethyl p-toluenesulfonate (74.2 mg,0.34 mmol) in DMF (1 mL) was slowly added, after the addition was completed, the reaction was stirred overnight at 70 ℃, the reaction was allowed to room temperature, 3mL of water was added, extraction with ethyl acetate, and the organic phase was collected, dried, concentrated, column chromatographed (dichloromethane: methanol=50:1 to 20:1) to give 74.1mg of a white solid product, yield: 70.59%.1H NMR (400 MHz, DMSO-d 6) δ10.27 (d, J=28.2 Hz, 2H), 8.86 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 7.66 (m, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 6.74 (s, 1H), 6.60 (d, J=8.6 Hz, 1H), 5.07 (d, J=6.2 Hz, 1H), 4.68 (s, 2H), 4.57 (t, J=5.1 Hz, 1H), 4.45 (t, J=5.1 Hz, 1H), 3.13 (m, 2H), 2.96 (s, 3H), 2.83 (s, 3H), 2.07 (d, J=9.7 Hz, 1H), 5.07 (d, J=9.7 Hz, 1H), 4.7 Hz, 1Hz, 62.386 Hz.
Example 4
Synthesis of Compound 28
Under ice bath, pyrazole-3-carboxylic acid (300 mg,0.45 mmol) and HATU (190.12 mg,0.5 mmol) were dissolvedTo 2mL of ldmf was added DIPEA (116.3 mg,0.9 mmol), which was reacted under ice bath for 40min, then compound 27 (285.7 mg,0.5 mmol) was dissolved in 2mL of ldmf and slowly dropped into the above reaction system, after the dropping was completed, reacted overnight at room temperature, the reaction was completed by TLC, 5mL of water was added, extraction was performed with ethyl acetate, and the organic phase was collected, dried, concentrated, and column chromatographed (dichloromethane: methanol=30:1 to 15:1) to give 101.8mg of an off-black solid product, yield: 34%. MS (ESI+): m/z calculated for C 28 H 29 BrN 10 O 5 ,664.1506；found,665.1585(M+H+)。
Example 5
Synthesis of Compound 29 (LY-33)
The synthesis procedure was as for compound 26, starting from compound 28, by column chromatography (dichloromethane: methanol=40:1 to 20:1) to give 35mg of a white solid in 66.69%. 1 H NMR(400MHz,DMSO-d6)δ9.99(d,J＝14.8Hz,2H),9.72(s,1H),9.12(s,1H),8.23(s,1H),8.10(s,2H),7.90(s,1H),7.64(s,1H),7.58(s,1H),7.36(s,2H),6.83(s,1H),6.76(s,1H),4.88(s,3H),4.78(s,1H),4.54(s,1H),4.47(s,1H),2.96(s,3H),2.82(s,3H),2.04(d,J＝15.9Hz,6H).13C NMR(101MHz,DMSO-D6)δ170.06,168.84,168.13,159.38,158.89,157.44,157.07,147.03,146.23,143.49,138.15,136.90,134.77,133.74,131.79,128.51,128.46,127.56,126.01,106.86,106.81,93.37,83.18,81.52,68.45,52.98,35.57,24.50,23.53,21.30.MS(ESI+):m/z calcd for C 30 H 32 BrFN 10 O 5 ,710.1725；found,711.1806(M+H+)
Example 6
Synthesis of Compound 14
The synthesis was carried out as in compound 25, starting from compound 13, and after completion of the reaction, by recrystallization (5 g, yellow solid, yield 78.8%). 1H NMR (600 MHz, DMSO-D6) delta 10.21 (s, 1H), 10.15 (s, 1H), 9.46 (s, 1H), 8.24 (m, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.69 (s, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 3.86 (s, 3H), 2.08 (s, 6H) & 13C NMR (151 MHz, DMSO-D6) delta 170.03,168.88,158.40,157.43,146.87,139.21,137.49,134.17,132.33,127.97,127.11,125.40,116.90,115.25,115.07,114.85,94.14, 57.24.50, 23.54.MS (ESI+) & m/cfac for N.72/C7 Br7.70, 35.50; found,530.0776 (m+h+).
Example 7
Synthesis of Compound 17
Compound 16 (2 g,3.26 mmol) was added to a high pressure autoclave, anhydrous dichloromethane (15 mL) and boron tribromide (1.63 g,6.52 mmol) were added, the reaction system was heated to 60 ℃ to react overnight, the reaction system was allowed to warm to room temperature, slowly depressurized, saturated sodium bicarbonate solution was slowly added dropwise until the reaction system was slightly alkaline, extracted with dichloromethane, the organic phase was collected, dried, concentrated, column chromatographed (dichloromethane: methanol=50:1 to 25:1) to give 1.17g of a white solid product, yield: 59.8%.1H NMR (400 MHz, DMSO-d 6) δ9.99 (d, J=9.6 Hz, 2H), 9.27 (s, 1H), 9.18 (s, 1H), 8.96 (s, 1H), 8.06 (d, J=5.6 Hz, 2H), 7.88 (s, 1H), 7.63 (d, J=10.9 Hz, 3H), 7.30 (d, J=9.3 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 3.25 (s, 2H), 2.49 (s, 2H), 2.04 (d, J=8.4 Hz, 6H), 1.75 (s, 3H).
Example 8
Synthesis of Compound 20
The above compound (500 mg,0.66 mmol), (2-bromoethoxy) -tert-butyldimethylsilane (189 mg,0.79 mmol), potassium carbonate (109.2 mg,0.79 mmol) were added to a 25mL round bottom flask, 5mL of LDMF was added to dissolve the starting material, and the reaction was allowed to proceed overnight at 70℃to completion by TLC detection, 10mL of water was added and extracted with ethyl acetate, the organic phase was collected, dried, concentrated, column chromatographed (dichloromethane: methanol) =50:1 to 20:1) to yield 400.1mg of white solid product, yield: 80.3%.1H NMR (400 MHz, DMSO-D6) delta 10.02 (s, 2H), 9.08 (s, 1H), 8.73 (s, 1H), 8.11 (s, 1H), 7.90 (s, 2H), 7.62 (s, 2H), 7.42 (D, J=7.2 Hz, 1H), 7.34 (D, J=7.4 Hz, 1H), 6.79 (m, 1H), 4.00 (s, 2H), 3.92 (s, 2H), 3.28 (s, 2H), 2.49 (s, 2H), 2.07 (D, J=7.3 Hz, 6H), 1.78 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H), 13C NMR (151 MHz, DMSO-D6) delta 170.00,169.93,169.69,169.61,169.52,168.75,168.66,158.87,158.78,157.46,157.06,144.60,136.88,133.87,130.18,127.60,116.78,115.09,113.10,100.00,70.96,62.11,35.63,29.51,26.35,24.47,23.11,18.55, -4.73.MS (ESI+) (m/z calcd for C33H45 Br3H, 378 O. 756.2415; found,757.2484 (M+H) + )
The product of the above step (400 mg,0.53 mmol) was added to a 10mL round bottom flask, anhydrous dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added, the reaction was complete by TLC at room temperature for 5 hours, the solvent was removed by concentration, and column chromatography (dichloromethane: methanol=50:1 to 20:1) gave 272.6mg of a white solid product, yield: 75%. 1 H NMR(400MHz,DMSO-d6)δ10.12(dd,J＝16.5,51.9Hz,3H),9.27(d,J＝48.2Hz,1H),9.03(d,J＝11.8Hz,1H),8.29(s,1H),7.99(s,1H),7.94(s,1H),7.71(s,1H),7.44(d,J＝14.6Hz,2H),7.09(s,1H),6.79(s,1H),3.93(s,2H),3.69(s,2H),3.26(s,2H),2.55(s,2H),2.05(s,6H),1.74(s,3H).
The product of the above step (200 mg,0.3 mmol) was added to a 10mL round bottom flask, anhydrous dichloromethane (3 mL) and triethylamine (91.1 mg,0.9 mmol) were added, the system was sonicated under ultrasound for 20 min to dissolve as much as possible part of the starting material, then p-toluenesulfonyl chloride (114.4 mg,0.6 mmol) was added and stirred at room temperature overnight, the reaction was concentrated and column chromatography (dichloromethane: methanol=50:1 to 25:1) afforded 30mg of the product as a white solid, yield: 12.54%.1H NMR (600 MHz, methanol-d 4) delta 8.02 (S, 2H), 7.71 (S, 2H), 7.64 (S, 1H), 7.45 (S, 1H), 7.29 (S, 2H), 7.19 (S, 1H), 6.68 (S, 1H), 4.39 (S, 2H), 4.19 (S, 2H), 3.47 (S, 2H), 2.62 (S, 2H), 2.34 (S, 3H), 2.12 (S, 6H), 1.90 (S, 3H) MS (ESI+):m/z calcd for C34H37BrN8O8S,796.1638; found,797.1704 (m+h+).
Example 9
Synthesis of Compound 21 (LY-22)
Compound 17 (60 mg,0.1 mmol), 1-bromo-3-fluoropropane (16.9 mg,0.12 mmol) and potassium carbonate (16.6 mg,0.12 mmol) were dissolved in DMF (2 mL), the reaction system was heated to 70℃and reacted overnight, the reaction was detected by TLC to be complete, water was added, extraction was performed with ethyl acetate, and the organic phase was collected, dried, concentrated and column chromatographed (dichloromethane: methanol=50:1 to 20:1) to give 40mg of a white solid in 60.65% yield. 1 H NMR(600MHz,DMSO-d6)δ10.05(m,2H),9.05(s,1H),8.84(s,1H),8.08(s,2H),7.88(s,1H),7.82(s,1H),7.59(s,2H),7.41(s,1H),7.30(s,1H),6.75(s,1H),4.65(s,1H),4.57(s,1H),3.99(s,2H),3.24(s,2H),2.09(s,2H),2.04(s,6H),1.74(s,3H). 13 C NMR(151MHz,DMSO-D6)δ170.00,169.85,169.74,168.84,158.84,157.40,157.16,144.92,137.04,133.84,131.91,127.82,127.53,116.91,115.76,115.29,112.69,100.00,82.14,81.07,65.18,36.69,35.74,30.37,24.47,23.53,23.10.MS(ESI+):m/z calcd for C28H32BrFN8O5,658.1663；found,659.1724(M+H+)
Example 10
Synthesis of Compound 18b
Compound 17 (200 mg,0.33 mmol) was dissolved in 2mL ldmf, diethylene glycol bis-p-toluenesulfonate (207.2 mg,0.5 mmol) and potassium carbonate (69.1 mg,0.5 mmol) were added, the reaction system was left to react at 70 ℃ for 10 hours, the reaction was checked to be complete by TLC, 4mL of water was added to the reaction system to room temperature, extraction was performed with ethyl acetate, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated, column chromatography (dichloromethane: methanol=60:1 to 35:1) to give 143.1mg of a white solid product, yield: 51.52%.1H NMR (600 MHz, DMSO-d 6) delta 10.07 (S, 2H), 9.15 (S, 1H), 8.79 (S, 1H), 8.17 (d, J=16.2 Hz, 1H), 7.91 (S, 2H), 7.77 (S, 2H), 7.65 (S, 2H), 7.43 (S, 3H), 7.35 (S, 1H), 6.78 (S, 1H), 4.16 (S, 2H), 3.98 (S, 2H), 3.69 (S, 4H), 3.27 (S, 2H), 2.36 (S, 3H), 2.07 (S, 6H), 1.77 (S, 3H) MS (ESI+):m/z calcd for C36H41BrN8O9S,840.1901; found,841.1981 (m+h+).
Example 11
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The compound diethylene glycol bis-p-toluenesulfonate (2 g,4.83 mmol) was dissolved in 15mL tetrahydrofuran, 5.8mL of ltbaf (1M solution in tetrahydrofuran) was added, the reaction was allowed to react at 50 ℃ for 9 hours, the reaction was complete by TLC detection, the solvent was removed by rotary evaporation, column chromatography (petroleum ether: ethyl acetate=10:1 to 5:1) gave 708.2mg of colorless oily liquid, yield: 55.9%.1H NMR (400 MHz, chloroform-d) delta 7.80 (t, J=6.4 Hz, 2H), 7.34 (d, J=6.1 Hz, 2H), 4.54 (S, 1H), 4.42 (S, 1H), 4.17 (S, 2H), 3.71 (S, 3H), 3.63 (S, 1H), 2.44 (S, 3H) 13C NMR (151 MHz, chloroform-d) delta 144.92,133.08,129.89,128.06,82.49,70.62,70.49,69.23,68.97.MS (ESI+):m/z calcd for C11H15FO4S,262.0675; found,285.0583 (m+na+).
Example 12
Synthesis of Compound 19b
Synthetic method the same as the synthesis of compound 20, starting from compound 17, was obtained by column chromatography (dichloromethane: methanol=50:1 to 20:1) to give 36mg of a white solid in 56% yield. 1H NMR (400 MHz, DMSO-D6) δ10.09 (D, J=18.0 Hz, 2H), 9.07 (s, 1H), 8.78 (s, 1H), 8.08 (s, 2H), 7.89 (D, J=11.2 Hz, 2H), 7.59 (D, J=12.0 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 6.77 (D, J=9.2 Hz, 1H), 4.58 (s, 1H), 4.46 (s, 1H), 4.04 (s, 2H), 3.75 (s, 3H), 3.67 (s, 1H), 3.24 (s, 2H), 2.48 (s, 2H), 2.04 (s, 6H), 1.74 (s, 3H). 13C NMR (151 MHz, DMSO-D6) delta 170.02,169.74,168.85,158.87,157.47,157.10,144.69,137.02,134.28,131.82,130.18,128.09,127.57,116.92,116.65,115.31,113.93,84.16,83.06,70.43,70.30,69.48,36.73,35.71,24.48,23.51,23.10.MS (ESI+): m/z calculated for C29H34BrFN8O6,688.1769; found,689.1849 (m+h+).
Example 13
Synthesis of Compound 18c
Synthetic method the same as the synthesis of compound 20, starting from compound 17, was obtained by column chromatography (dichloromethane: methanol=50:1 to 20:1) as 50mg of a white solid in 49% yield. 1H NMR (400 MHz, DMSO-d 6) delta 9.99 (S, 2H), 9.06 (S, 1H), 8.75 (S, 1H), 8.08 (S, 2H), 7.86 (d, J=16.5 Hz, 2H), 7.73 (t, J=6.0 Hz, 2H), 7.60 (S, 2H), 7.42 (d, J=10.3 Hz, 2H), 7.36 (d, J=9.8 Hz, 1H), 7.31 (d, J=9.6 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.06 (S, 2H), 4.00 (S, 2H), 3.67 (S, 2H), 3.54 (S, 2H), 3.51 (S, 2H), 3.45 (S, 2H), 3.23 (d, J=11.9 Hz, 2H), 2.43 (S, 2H), 35 (S, 2.6 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 4.06 (S, 2H), 4.00 (S, 2H), 3.67 (S, 2H), 3.54 (S, 2H), 3.45 (S, 3.23 (d, 3.43 (3H), 3.35 (3S, 2H), 3.45S, 3.38 (3H), 3.38 (3S, 38); found,885.2238 (m+h+).
Example 14
Synthesis of Compound 19c
Synthetic method the same as the synthesis of compound 20, starting from compound 17, was obtained by column chromatography (dichloromethane: methanol=50:1 to 20:1) to yield 26mg of a white solid in 65% yield. 1H NMR (400 MHz, DMSO-d 6) delta 10.26 (s, 1H), 10.16 (s, 1H), 9.06 (s, 1H), 8.81 (s, 1H), 8.08 (s, 2H), 7.90 (d, J=26.0 Hz, 2H), 7.60 (d, J=14.3 Hz, 2H), 7.44 (s, 1H), 7.30 (s, 1H), 6.78 (s, 1H), 4.52 (s, 1H), 4.40 (s, 1H), 4.02 (s, 2H), 3.71 (s, 2H), 3.64 (s, 1H), 3.57 (d, J=14.0 Hz, 6H), 3.25 (s, 2H), 3.12 (s, 1H), 2.04 (s, 6H), 1.74 (s, 3H), MS (ESI+):m/z calcd for C 31 H 38 BrFN 8 O 7 ,732.2031；found,755.1894(M+Na + ).
Example 15
Synthesis of Compound LY-14
Compound 13 (3 g,7.53 mmol), p-methoxyaniline (1.11 g,9.04 mmol), p-toluenesulfonic acid monohydrate (572.56 mg,3.01 mmol) were added to a 100mL round bottom flask, 40mL of isopropanol was added as a reaction solvent, the reaction system was left to react overnight at 90 ℃, the reaction was detected to be complete by TLC, the reaction system was slowly poured into 200mL of ethyl acetate at room temperature, a solid was precipitated, the filter cake was washed with ethyl acetate, and the filter cake was dried to give 2.6g of a white solid product, yield: 71.18%.1H NMR (400 MHz, DMSO-d 6) delta 10.17 (s, 1H), 10.09 (s, 1H), 9.71 (s, 1H), 8.78 (s, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.34 (d, J=9.5 Hz, 2H), 6.75 (d, J=6.5 Hz, 2H), 3.70 (s, 3H), 2.08 (s, 6H) MS (ESI+):m/z calcd for C 21 H 21 BrN 6 O 3 ,484.0859；found,485.0935(M+H + ).
Example 16
Synthesis of Compound LY-15
The starting compound LY-14 (2 g,4.12 mmol) was added to a high pressure autoclave, anhydrous dichloromethane (15 mL) and boron tribromide (1.55 g,6.18 mmol) were added, the reaction system was heated to 60℃for reaction overnight, the reaction system was allowed to react at room temperature, slowly depressurized, the reaction system was slowly added dropwise to saturated sodium bicarbonate solution to make the final solution slightly alkaline, extracted with dichloromethane, the organic phase was collected, dried, concentrated, and column chromatographed (dichloromethane: methanol=50:1 to 35:1) to give 1.23g of a white solid product, yield: 63.11%.1H NMR (400 MHz, DMSO-d 6) δ10.10 (s, 1H), 8.94 (s, 1H), 8.09 (s, 1H), 7.73 (s, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.39 (m, 1H), 7.30 (d, J=9.9 Hz, 2H), 6.54 (q, J=9.1, 11.7Hz, 2H), 2.08 (s, 6H).
Example 17
Synthesis of Compound LY-16
Synthetic method the same as the synthesis of compound 20, starting from compound LY-15 (1 g,2.12 mmol), (2-bromoethoxy) -tert-butyldimethylsilane, column chromatography (petroleum ether: ethyl acetate=5:1 to 1:1) gives 1.04g of the product as a white solid, yield: 78%.
The product of the above step (1.04 g,1.65 mmol) was added to a 25mL round bottom flask, 1, 4-dioxane solution (10 mL) and 4 mol hydrogen chloride-dioxane solution (10 mL) were added respectively, then stirred at room temperature for 6 hours, the reaction was complete by TLC detection, filtration, washing of the filter cake with 1, 4-dioxane, and drying to give the product (747.3 mg, white solid, yield: 88%). 1H NMR (400 MHz, DMSO-d 6) δ10.11 (s, 1H), 10.06 (s, 1H), 9.11 (s, 1H), 8.13 (s, 2H), 7.72 (s, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.42 (d, J=9.0 Hz, 3H), 6.72 (m, 2H), 4.03 (m, 1H), 3.90 (s, 2H), 3.69 (s, 2H), 2.09 (s, 6H) MS (ESI+) 22 H 23 BrN 6 O 4 ,514.0964；found,515.1030(M+H + ).
Example 18
Synthesis of Compound LY-17
Compound LY-16 (700 mg,1.36 mmol) was added to a 10mL round bottom flask, anhydrous dichloromethane (2 mL) and anhydrous triethylamine (688.1 mg,6.8 mmol) were added, p-toluenesulfonyl chloride (518.6 mg,2.72 mmol) was dissolved in anhydrous dichloromethane (1 mL) and slowly added dropwise to the reaction system, which was stirred at room temperature for 12 hours after the dropwise addition was completed, the reaction was completed by TLC detection, 5mL water quenching reaction was added, extracted with dichloromethane, the organic phase was collected, dried, concentrated, recrystallized (methanol) to give 602.6mg of a white solid product, yield: 66.18%. 1 H NMR(600MHz,DMSO-d6)δ10.03(m,1H),9.98(s,1H),9.08(s,1H),8.11(s,1H),7.75(s,2H),7.67(s,1H),7.55(s,1H),7.41(s,3H),7.35(s,2H),6.59(s,2H),4.26(s,2H),4.04(s,2H),2.35(s,3H),2.03(s,6H). 13 C NMR(101MHz,DMSO-D6)δ170.01,168.87,158.65,157.52,157.31,152.77,145.53,137.25,134.58,132.70,132.26,130.68,128.16,127.34,120.74,116.72,115.07,114.71,100.00,69.69,65.96,24.52,23.57,21.60.MS(ESI+):m/z calcd for C29H29BrN6O6S,668.1053；found,669.1119(M+H+).
Example 19
Synthesis of Compound LY-18
To a solution of compound LY-17 (200 mg,0.3 mmol) in DMF (2 mL) was added potassium carbonate (4.1 mg,0.03 mmol), K 2.2.2 (112.9 mg,0.3 mmol) and KF (34.9 mg,0.6 mmol), and then the reaction system was allowed to react at 100℃for 1h. The reaction solution was concentrated and subjected to column chromatography (dichloromethane: methanol=60:1 to 30:1) to give a product (128.2 mg, white solid, yield 82.6%); 1H NMR (600 MHz, DMSO-D6) delta 10.09 (s, 1H), 10.04 (s, 1H), 9.08 (s, 1H), 8.10 (s, 2H), 7.67 (s, 1H), 7.56 (s, 1H), 7.41 (s, 3H), 6.71 (s, 2H), 4.71 (s, 1H), 4.63 (s, 1H), 4.14 (s, 1H), 4.09 (s, 1H), 2.04 (s, 6H) 13C NMR (151 MHz, DMSO-D6) delta 170.00,168.88,158.72,157.56,157.32,153.29,137.26,134.51,132.21,127.42,120.90,116.78,115.19,114.73,83.32,82.22,67.78,67.66,24.52,23.54.MS (ESI+) -C/cfz/lc D 22 H 22 BrFN 6 O 3 ,516.0921；found,517.0988(M+H+).
Example 19
5-bromo-2, 4-dichloropyrimidine (15 g,65.83 mmol), 2-amino-N-methylbenzamide (11.86 g,79 mmol), potassium carbonate (10.92 g,79 mmol) were added to a 500mL round bottom flask, DMF (200 mL) was added and the system was allowed to react at 70℃for 15 hours, the reaction was complete by TLC detection, and when the reaction system was allowed to come to room temperature, 500mL of water was added, a yellow solid precipitated, the filtration was performed, the filter cake was washed with water, and dried to give a yellow solid product (19.94 g, yield: 88.68%).
The product of the above step (6 g,17.56 mmol), p-methoxyaniline (2.59 g,21.07 mmol), p-toluenesulfonic acid monohydrate (1.34 g,7.02 mmol) were added to a 250mL round bottom flask, 100mL of isopropanol was added as a reaction solvent, the reaction system was left to react overnight at 90 ℃, the reaction was checked by TLC to completion, the reaction system was slowly poured into 200mL of ethyl acetate with solid precipitation, filtration, washing the filter cake with ethyl acetate, oven drying without purification to give 6.02g of pale yellow solid, the obtained filter cake was added to a high pressure reaction vessel, anhydrous dichloromethane (40 mL) and boron tribromide (5.28 g,21.09 mmol) were added, the reaction vessel was left to react for 4 hours at 60 ℃, the reaction vessel was allowed to stand at room temperature, saturated sodium bicarbonate solution was slowly dropped under reduced pressure and the final solution was made basic, the organic phase was collected, dried, concentrated, the column (dichloromethane: methanol=60:1 to 35:1) to give 2.62g of white solid product in two steps, yield: 36.02%. 1H NMR (600 MHz, DMSO-d 6) δ11.28 (s, 1H), 9.08 (s, 1H), 9.03 (s, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.17 (s, 1H), 7.68 (s, 1H), 7.37 (s, 1H), 7.34 (s, 2H), 7.08 (s, 1H), 6.66 (s, 2H), 2.77 (s, 3H): m/z calcd for C18H16BrN5O2,413.0487; found,414.0557 (m+h+).
The synthesis method is the same as that of the compound 20, the product (2 g,4.83 mmol) of the above step (2-bromoethoxy) -tert-butyldimethylsilane is taken as a raw material, the white solid product obtained by column chromatography separation and purification in the first step is reacted in the second step, and the compound (930.4 mg, white solid, two-step yield: 42.01%) is obtained by recrystallization. 1H NMR (600 MHz, DMSO-d 6) δ11.32 (s, 1H), 9.22 (s, 1H), 8.68 (s, 1H), 8.61 (s, 1H), 8.20 (s, 1H), 7.69 (s, 1H), 7.47 (s, 2H), 7.41 (s, 1H), 7.08 (s, 1H), 6.82 (s, 2H), 3.95 (s, 2H), 3.87 (s, 2H), 2.77 (s, 3H), 0.84 (s, 9H), 0.04 (s, 6H) MS (ESI+):m/z calcd for C26H34BrN5O3Si,571.1614; found,572.1692 (m+h+).
The product of the above step (800 mg,1.75 mmol) was taken as starting material and taken by column chromatography (petroleum ether: ethyl acetate=3:1 to 1:2) to give 673.8mg of the product as a white solid in 63% yield. 1H NMR (400 MHz, DMSO-D6) δ11.34 (s, 1H), 9.29 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 8.24 (s, 1H), 7.80 (m, 2H), 7.72 (D, J=6.7 Hz, 1H), 7.50 (D, J=10.6 Hz, 5H), 7.13 (D, J=8.3 Hz, 1H), 6.77 (t, J=7.2 Hz, 2H), 4.33 (s, 2H), 4.13 (s, 2H), 2.80 (s, 3H), 2.41 (s, 3H) 13C NMR (151 MHz, DMSO-D6) δ169.34,158.86,158.06,156.30,153.48,145.53,139.78,134.27,132.83,131.81,130.70,128.44,128.20, 128.128, 128, 122, 122.66, 122, 16+12.121, 12.121, 12.33, 12.12.12, 12.12.12+12.12, 12.41 (s, 3H), 12.41 (12.41, 3H). M/z calcd for C 27 H 26 BrN 5 O 5 S,611.0838；found,612.0916(M+H+).
Synthesis of Compound LY-3:
the synthesis method is the same as that of the compound LY-18. The nuclear magnetic data of LY-3 were 1H NMR (400 MHz, DMSO-D6) δ11.34 (s, 1H), 9.29 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 7.72 (m, 1H), 7.54 (D, J=6.6 Hz, 2H), 7.48 (m, 1H), 7.13 (s, 1H), 6.91 (D, J=6.2 Hz, 2H), 4.80 (s, 1H), 4.68 (s, 1H), 4.24 (s, 1H), 4.16 (s, 1H), 2.81 (s, 3H) 13C (101 MHz, DMSO-D6) δ169.34,158.88,158.09,156.30,153.93,139.80,134.13,131.85,128.45,122.49,122.18,122.12, 122.121, 121.61, 61, 61.83, 67.82, and 98.79+12.98.79.85.39.39.39.8 (S, 12.11). M/z calcd for C 20 H 19 BrFN 5 O 2 ,459.0706；found,460.0783(M+H+).
Compound 1 (1 g,2.93 mmol), 4-aminophenylether (441.7 mg,3.22 mmol) and p-toluenesulfonic acid monohydrate (222.6 mg,1.17 mmol) were added to a reaction flask, isopropanol (20 mL) was added, heated to 80℃and stirred overnight, after completion of the reaction, the reaction mixture was slowly poured into water (100 mL) at room temperature to precipitate a white solid, and the product was obtained by filtration and drying (white solid, yield: 76.65%). 1 H NMR(600MHz,DMSO-d6)δ11.30(s,1H),9.22(s,1H),8.69(s,1H),8.61(s,1H),8.20(s,1H),7.68(s,1H),7.44(d,J＝25.6Hz,3H),7.09(s,1H),6.80(s,2H),3.95(s,2H),2.77(s,3H),1.28(s,3H).
Example 20
4-nitrophenol (5 g,45.82 mmol), bromoethanol (6.87 g,54.98 mmol), potassium carbonate (7.6 g,54.98 mmol) were dissolved in DMF (100 mL) and isolated and purified by column chromatography (petroleum ether: ethyl acetate=5:1 to 2:1) to give 6.23g of yellow solid product, yield: 72%. MS (ESI) + ):m/z calcd for C 8 H 9 NO 4 ,183.0532；found,184.1054(M+H + ).
The synthesis procedure was as above, starting from 4-nitrophenol (5 g,45.82 mmol) and by column chromatography (petroleum ether: ethyl acetate=5:1 to 2:1) gave 6.87g of the product as a yellow solid, yield: 66%.1H NMR (400 MHz, chloroform-d) δ8.18 (q, J=10.2, 13.6Hz, 2H), 6.98 (d, J=8.3 Hz, 2H), 4.22 (s, 2H), 3.89 (s, 2H), 3.76 (s, 2H), 3.67 (s, 2H): m/z calcd for C 10 H 13 NO 5 ,227.0794；found,228.1395(M+H+).
Synthetic method the same as the synthesis of compound 25, starting from compound 1 (1 g,2.93 mmol), was subjected to column chromatography (dichloromethane: methanol=50:1 to 20:1) to give compound 4b (white solid, yield: 59.8%). 1H NMR (400 MHz, DMSO-d 6) δ11.33 (s, 1H), 9.27 (s, 1H), 8.72 (s, 1H), 8.64 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.51 (s, 2H), 7.48 (d, J=8.9 Hz, 1H), 7.13 (s, 1H), 6.87 (s, 2H), 4.60 (s, 1H), 4.06 (s, 2H), 3.73 (s, 2H), 3.51 (s, 4H), 2.81 (s, 3H).
Compound 4b (502.4 mg,1 mmol), p-toluenesulfonic acidAcyl chloride (190.7 mg,1 mmol) and triethylamine (121.3 mg,1.2 mmol) were added to a reaction flask, dissolved in anhydrous dichloromethane (6 mL), the reaction system was stirred at room temperature for 16 hours, quenched with 15mL of water, extracted with dichloromethane, the organic phase was collected, dried, concentrated, and column chromatographed (dichloromethane: methanol=50:1 to 30:1) to give product 5b (white solid, yield: 56%). 1H NMR (400 MHz, methanol-D4) delta 8.57 (s, 1H), 8.08 (s, 1H), 7.75 (s, 2H), 7.60 (s, 1H), 7.36 (D, J=24.1 Hz, 5H), 7.08 (s, 1H), 6.83 (s, 2H), 4.16 (s, 2H), 4.00 (s, 2H), 3.71 (s, 4H), 2.89 (s, 3H), 2.35 (s, 3H) 13C NMR (101 MHz, CHLOFORM-D) delta 169.46,156.78,155.19,144.93,139.17,133.04,132.18,131.73,129.91,128.05,126.76,122.94,122.91,122.86,122.14,114.94,100.00,70.03,69.31,69.01,67, 67.27, 21.02C NMR (101 MHz, 133.04,132.18,131.73, 132.73, 129.91,128.05, 122.94, 122.86, 122.94, 122.00/7.02) ESC (S/C/ESZ) 29 H 30 BrN 5 O 6 S,655.1100；found,656.1162(M+H+).
The synthesis method is the same as that of LY-18, and compound 6b (white solid, yield: 70.6%) can be obtained by column chromatography (dichloromethane: methanol=100:1 to 35:1) using compound 5b as raw material. 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.22(s,1H),8.67(s,1H),8.61(d,J＝8.4Hz,1H),8.20(s,1H),7.68(d,J＝8.5Hz,1H),7.48(d,J＝8.6Hz,2H),7.42(d,J＝8.2Hz,1H),7.08(t,J＝5.8Hz,1H),6.84(d,J＝8.7Hz,2H),4.57(s,1H),4.45(s,1H),4.04(s,2H),3.73(s,3H),3.65(s,1H),2.77(s,3H). 13 C NMR(101MHz,DMSO-D6)δ169.34,158.90,158.07,156.29,154.24,139.80,133.87,131.83,128.44,122.46,122.15,121.60,114.83,84.41,82.77,70.33,69.61,67.82,26.84.
Example 21
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The nitro compound (2 g,7.37 mmol), iron powder (617.7 mg,11.06 mmol), ammonium chloride (591.63 mg,11.06 mmol) were added to a reaction flask, and methanol (10 mL), water (5 mL), tetrahydrofuran were added(10 mL), the reaction was stirred at 73℃for 6 hours, and the reaction was complete by TLC, filtered while hot, and the filtrate was concentrated and column chromatographed (petroleum ether: ethyl acetate=3:1 to 1:1) to give the product (black solid, yield: 70.5%). The product (black solid) was obtained by filtration through celite and concentration, yield: 80%. MS (ESI+): m/z calculated for C 12 H 19 NO 4 ,241.1314；found,242.1922(M+H + ).
Synthetic method the same as the synthesis of compound 4b, starting from compound 1, was subjected to column chromatography (dichloromethane: methanol=50:1 to 20:1) to give compound 4c (white solid, yield: 59.8%). MS (ESI+): m/z calculated for C 24 H 28 BrN 5 O 5 ,545.1274；found,546.1349(M+H + ).
The synthesis procedure was the same as that for compound 5b, starting from compound 4c, and subjecting it to column chromatography (dichloromethane: methanol=50:1 to 30:1) to give the product (white solid, yield: 60%). 1 H NMR(600MHz,Chloroform-d)δ10.93(s,1H),8.53(s,1H),8.11(s,1H),7.76(s,2H),7.44(m,1H),7.37(s,2H),7.33(s,1H),7.28(s,3H),7.01(s,1H),6.83(s,2H),6.39(s,1H),4.13(s,2H),4.08(s,2H),3.79(s,2H),3.65(s,4H),3.59(s,2H),2.97(s,3H),2.39(s,3H). 13 C NMR(151MHz,CHLOROFORM-D)δ169.61,158.51,156.95,156.57,154.92,144.97,139.52,133.00,132.77,131.58,129.93,128.03,128.01,126.90,122.59,122.38,121.89,114.92,95.03,70.86,70.81,69.94,69.38,68.80,67.87,26.95,21.70.MS(ESI+):m/z calcd for C 31 H 34 BrN 5 O 7 S,699.1362；found,700.1400(M+H + ).
The synthesis method of the compound LY-10 is the same as that of the compound 6b, and the compound 5c is taken as a raw material, and a white solid product is obtained through column chromatography (dichloromethane: methanol=50:1 to 25:1), and the yield is: 65%. 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),9.22(s,1H),8.68(s,1H),8.61(s,1H),8.20(s,1H),7.69(s,1H),7.47(s,2H),7.43(s,1H),7.08(d,J＝7.7Hz,1H),6.83(s,2H),4.54(s,1H),4.42(s,1H),4.02(s,2H),3.64(m,8H),2.76(s,3H). 13 C NMR(101MHz,DMSO-D6)δ169.34,158.89,156.29,154.26,139.80,133.83,131.82,128.43,122.45,122.14,121.60,114.81,84.39,82.75,70.45,70.39,70.14,69.60,67.82,26.84.MS(ESI+):m/z calcd for C 24 H 27 BrFN 5 O 4 ,547.1230；found,548.1299(M+H + ).
Example 21
Triethylene glycol (10 g,66.59 mmol), imidazole (2.72 g,39.95 mmol) were added to a 500mL round bottom flask under ice bath, the starting material was dissolved with anhydrous dichloromethane (150 mL), a dichloromethane solution of t-butyldimethylchlorosilane (5.02 g TBS-Cl was slowly added dropwise in 50mL anhydrous dichloromethane), after the addition was completed, the reaction system was warmed to room temperature and stirred for 12 hours, the reaction was completed by TLC detection, the reaction system was poured into 200mL water, extracted with dichloromethane, the organic phase was collected, washed with saturated ammonium chloride and saturated saline respectively, the organic phase was dried, concentrated, column chromatographed (petroleum ether: ethyl acetate=3:1 to 1:1) to give 11.62g colorless oil, yield: 66%. MS (ESI+): m/z calculated for C 12 H 28 O 4 Si,264.1757；found,265.2788(M+H + ).
Compound 30c (1 g,3.78 mmol), p-toluenesulfonyl chloride (865.6 mg,4.54 mmol), triethylamine (459.4 mg,4.54 mmol) were dissolved in dichloromethane (15 mL), and the reaction system was stirred at room temperatureThe reaction was quenched with 30mL of water for 15 hours, extracted with dichloromethane, and the organic phase was collected, dried, concentrated, and column chromatographed (petroleum ether: ethyl acetate=10:1 to 5:1) to give the product (colorless oil, yield: 66.8%). MS (ESI+): m/z calculated for C 23 H 39 N 3 O 8 Si,513.2506；found,514.2583(M+H + ).
Compound 33c (1 g,1.95 mmol) was dissolved in DMF (10 mL), potassium tert-butoxide (547.6 mg,4.88 mmol) was slowly added, stirred at 0deg.C for 40 min, methyl iodide (692.7 mg,4.88 mmol) was dissolved in DMF (5 mL) and slowly added dropwise to the above reaction system, after the addition was completed, the reaction system was left at 30deg.C for 3 hours, the reaction was detected to be complete by TLC, the reaction system was poured into ice water and extracted with ethyl acetate, the organic phase was collected, concentrated, and column chromatography (dichloromethane: methanol=50:1 to 30:1) gave compound 34c (yellow solid, yield: 76%).
Compound 34c (2 g,3.69 mmol), iron powder (309.4 mg,5.54 mmol), ammonium chloride (296.33 mg,5.54 mmol) were added to a reaction flask, methanol (10 mL), water (5 mL), tetrahydrofuran (10 mL) were added, the reaction system was stirred at 73℃for 6 hours, the reaction was completed by TLC detection, the hot filtrate was filtered, and the filtrate was concentrated to give compound 35c (black solid, yield: 70.5%) by column chromatography (petroleum ether: ethyl acetate=3:1 to 1:1).
Compound 13 (1 g,2.51 mmol), 35c (1.28 g,2.51 mmol) and p-toluenesulfonic acid monohydrate (190.22 mg,1 mmol) were added to a reaction flask, isopropanol (20 mL) was added, the reaction system was stirred at 80deg.C overnight, and the reaction was allowed to proceed to completion The reaction system was cooled to room temperature, poured into water (100 mL), the existing pale yellow solid was precipitated, filtered and dried to obtain compound 36c, the dried compound was dissolved in anhydrous dichloromethane (10 mL), trifluoroacetic acid (10 mL) was slowly added, the reaction system was stirred at room temperature for 6 hours, after the reaction was completed, the solvent was removed by rotary evaporation, and compound 37c (white solid, two-step yield: 66%) was obtained by column chromatography (dichloromethane: methanol=50:1 to 20:1). 1H NMR (600 MHz, DMSO-d 6) delta 10.05 (s, 2H), 9.16 (s, 1H), 8.13 (s, 2H), 7.66 (s, 1H), 7.49 (s, 2H), 7.36 (d, J=35.0 Hz, 2H), 6.89 (s, 1H), 4.52 (s, 1H), 4.03 (s, 2H), 3.65 (s, 2H), 3.51 (s, 2H), 3.44 (s, 2H), 3.37 (s, 6H), 2.91 (s, 3H), 2.64 (d, J=131.7 Hz, 3H), 2.05 (s, 6H), 1.81 (s, 3H). MS (ESI+) 33 H 43 BrN 8 O 8 ,758.2387；found,759.2467(M+H+).
Compound 37c (100 mg,0.13 mmol), p-toluenesulfonyl chloride (30.5 mg,0.16 mmol), triethylamine (26.29 mg,0.26 mmol) were dissolved in anhydrous dichloromethane (2 mL) and reacted at room temperature for 16 hours, the starting materials were reacted completely, the solvent was removed by concentration, and compound 38c (white solid, yield: 56%) was obtained by column chromatography (dichloromethane: methanol=50:1 to 20:1). 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),9.95(s,1H),9.22(s,1H),8.18(d,J＝5.8Hz,2H),7.77(s,2H),7.70(s,1H),7.54(d,J＝10.9Hz,2H),7.46(s,2H),7.38(s,2H),6.91(m,1H),4.09(s,2H),4.04(s,2H),3.65(s,2H),3.55(s,2H),3.48(s,2H),3.44(s,2H),3.36(s,2H),2.93(s,3H),2.55-2.77(s,3H),2.40(s,3H),2.07(s,8H),1.83(s,3H).MS(ESI+):m/z calcd for C 40 H 49 BrN 8 O 10 S,912.2476；found,913.2554(M+H + ).
Compound 38c (40 mg, 43.77. Mu. Mol) was dissolved in tetrahydrofuran (0.5 mL), and a 0.5mL1M TBAF solution was added thereto, and the reaction system was left at 50 ℃ The reaction was stirred overnight, cooled to room temperature, 2mL of water was added, extracted with ethyl acetate, and the organic phase was collected, concentrated, and subjected to column chromatography (dichloromethane: methanol=30:1 to 15:1) to give compound 39c (white solid, yield: 62%). 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.91(s,1H),9.18(s,1H),8.14(d,J＝4.6Hz,2H),7.66(s,1H),7.47(d,J＝18.3Hz,2H),7.37(d,J＝13.0Hz,2H),6.89(s,1H),4.52(s,1H),4.40(s,1H),4.03(s,2H),3.64(d,J＝11.7Hz,3H),3.53(d,J＝12.1Hz,5H),3.33(s,2H),2.90(s,3H),2.64(d,J＝88.9Hz,3H),2.04(s,8H),1.80(s,3H).MS(ESI + ):m/z calcd for C 33 H 42 BrFN 8 O 7 ,760.2344；found,761.2425(M+H + ).
Example 22
Compound 32 (2 g,7.48 mmol), fluoroethyl p-toluenesulfonate (1.96 g,8.98 mmol), potassium carbonate (1.24 g,8.98 mmol) were dissolved in DMF (20 mL), the reaction was left to react at 70℃for 6 hours, the reaction was detected by TLC, 50mL of water was added, extraction was performed with ethyl acetate, and the organic phase was collected, dried, concentrated, and chromatographed on column (petroleum ether: ethyl acetate=5:1 to 2:1) to give compound 40 (yellow solid, yield: 76.5%).
2, 4-dichloro-5-trifluoromethylpyrimidine (164.9 mg,0.76 mmol) was dissolved in 1, 2-dichloroethane (1.5 mL) and t-butanol (1.5 mL) at 0deg.C, 1M zinc chloride in diethyl ether (1.67 mL) was added and then stirred at this temperature for 1 hour, 41 (180 mg,0.76 mmol) was added to the reaction system, triethylamine (85 mg,0.84 mmol) was dissolved in 1, 2-dichloroethane (0.75 mL) and t-butanol (0.75 mL) and slowly added to the reaction system, after the dropwise addition was completed, the mixture was warmed to room temperature and stirred overnight, the raw materials were detected to be reacted completely, water-quenched, extracted with dichloromethane, dried organic phase, concentrated and column chromatographed (petroleum ether: ethyl acetate) Ethyl acetate=5:1 to 1:1) to give the product (white solid, yield: 36.5%). 1 H NMR(400MHz,DMSO-d6)δ10.46(s,1H),9.00(s,1H),8.69(s,1H),8.15(s,1H),7.87(s,1H),7.33(s,1H),7.04(s,1H),4.80(s,1H),4.68(s,1H),4.27(s,1H),4.20(s,1H),3.21(s,2H),1.75(s,3H).MS(ESI + ):m/z calcd for C 18 H 18 ClF 4 N 5 O 3 ,463.1034；found,464.3339(M+H + ).
Compound 42 (100 mg,0.22 mmol), 2, 4-dinitroaniline (47.6 mg,0.26 mmol) and potassium carbonate (35.9 mg,0.26 mmol) were dissolved in DMF (2 mL), the reaction system was left to react at 60℃for 20 hours, the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was collected, dried, concentrated and column chromatographed (dichloromethane: methanol=100:1 to 40:1) to give the product (yellow solid, yield: 26.9%).
Compound 43 (100 mg,0.16 mmol), iron powder (13.4 mg,0.24 mmol), ammonium chloride (12.7 mg,0.24 mmol) were added to a reaction flask, methanol (2 mL), water (1 mL), tetrahydrofuran (2 mL) were added, the reaction system was stirred at 70℃for 6 hours, the reaction was detected by TLC and was complete, hot filtration was performed, the filtrate was concentrated, dissolved in anhydrous tetrahydrofuran and placed under an ice bath, triethylamine (32.4 mg,0.32 mmol) was added dropwise, acetyl chloride (25.1 mg,0.32 mmol) was added, the reaction system was stirred at room temperature for 1 hour after the addition was completed, water quenching was added, extraction was performed with ethyl acetate, the organic phase was dried, and concentrated and column chromatography (dichloromethane: methanol=50:1 to 25:1) gave compound 44 (white solid, two-step yield: 32.8%). 1H NMR (600 MHz, DMSO-d 6) δ10.06 (d, J=22.7 Hz, 2H), 9.48 (s, 1H), 8.89 (d, J=24.0 Hz, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.85 (s, 2H), 7.53 (d, J=30.9 Hz, 2H), 7.40 (s, 1H), 7.29 (s, 1H), 6.74 (s, 1H), 4.74 (d, J=24.0 Hz, 2H), 4.17 (d, J=29.7 Hz, 2H), 3.25 (s, 2H), 2.49 (s, 2H), 2.04 (s, 3H) ),2.00(s,3H),1.74(s,3H).MS(ESI + ):m/z calcd for C 28 H 30 F 4 N 8 O 5 ,634.2275；found,635.2350(M+H + ).
Example 23
Compound 25 (200 mg,0.39 mmol), triethylene glycol bis-p-toluenesulfonate (270.5 mg,0.59 mmol), potassium carbonate (81.5 mg,0.59 mmol) were dissolved in DMF (5 mL), the reaction system was left to react for 6 hours at 60 ℃, the starting materials were detected to be complete, the solvent was removed by concentration, and compound LY-19 was obtained by column chromatography (dichloromethane: methanol=60:1 to 30:1) as a yellow solid, yield: 69%.1H NMR (600 MHz, DMSO-D6) δ10.03 (s, 2H), 9.46 (s, 1H), 8.22 (D, J=19.4 Hz, 2H), 8.01 (s, 1H), 7.75 (D, J=12.7 Hz, 3H), 7.70 (s, 1H), 7.52 (s, 1H), 7.45 (s, 2H), 7.38 (s, 1H), 7.13 (s, 1H), 4.16 (s, 2H), 4.09 (s, 2H), 3.69 (s, 2H), 3.56 (s, 2H), 3.52 (s, 2H), 3.45 (s, 2H), 2.39 (s, 3H) 13C NMR (101 MHz, DMSO-D6) delta 170.04,168.86,158.36,157.47,145.92,145.41,139.74,137.48,134.41,132.91,132.43,130.63,128.08,127.04,125.07,116.81,116.17,115.14,114.79,70.49,70.43,70.20,69.82,69.22,68.41,24.51,23.58,21.59.MS (ESI+). M/z calcd for C 33 H 36 BrN 7 O 10 S,801.1428；found,802.1494(M+H+).
The synthesis method is the same as that of the compound 39c, and the compound LY-19 is taken as a raw material, and the product is obtained through column chromatography (dichloromethane: methanol=50:1 to 30:1), and is yellow solid, and the yield is: 66.5%. 1 H NMR(600MHz,DMSO-d6)δ10.01(s,2H),9.42(s,1H),8.17(d,J＝17.5Hz,2H),7.96(s,1H),7.69(s,1H),7.66(s,1H),7.48(s,1H),7.34(s,1H),7.09(s,1H),4.49(s,1H),4.41(s,1H),4.14(s,2H),3.69(s,2H),3.62(s,1H),3.56(s,3H),3.52(s,2H),2.03(s,6H). 13 C NMR(151MHz,DMSO-D6)δ170.06,168.89,158.36,157.51,145.92,139.77,137.48,134.39,132.42,128.02,127.08,125.08,116.84,116.19,115.19,114.79,84.10,83.00,70.56,70.31,70.21,69.87,69.24,24.48,23.56.MS(ESI + ):m/z calcd for C 26 H 29 BrFN 7 O 7 ,649.1296；found,650.1373(M+H + ).
Example 24
Synthesis of LY-21
Compound 6-fluoronicotinic acid (141.1 mg,1 mmol), HATU (456.29 mg,1.2 mmol) were dissolved in DMF (2 mL), DIPEA (155.1 mg,1.2 mmol) was added and reacted at room temperature for 40 min, then compound 15 (500 mg,1 mmol) was added to the reaction system and the reaction was continued at room temperature for 10 h, after complete reaction of the starting materials, 5mL of water was added, extracted with ethyl acetate, the organic phase was collected, dried, concentrated, and purified by column chromatography (dichloromethane: methanol=50:1 to 30:1) to give the product in the yield: 66.3%. 1 H NMR(600MHz,DMSO-d6)δ10.02(s,1H),9.90(s,1H),9.66(s,1H),9.16(s,1H),8.74(s,1H),8.41(s,1H),8.13(s,1H),8.11(s,1H),7.70(s,1H),7.59(s,2H),7.42(s,1H),7.35(s,1H),7.30(s,1H),6.83(s,1H),3.73(s,3H),2.06(s,3H),1.98(s,3H).MS(ESI+):m/z calcd for C 27 H 24 BrFN 8 O 4 ,622.1088；found,623.1164(M+H + ).
Example 25
3-cyano-2-fluoropyridine (10 g,81.9 mmol), N-methylmethanesulfonamide (9.83 g,90.07 mmol), potassium carbonate (22.6 g,163.53 mmol) were added to a 500mL round bottom flask, DMF (200 mL) was added, the reaction system was allowed to react at 70℃for 3 hours, the reaction was complete by TLC, the reaction system was allowed to slowly add to 1 liter of water at room temperature, and allowed to stand with a white solid precipitated, and filtered to give 13.89g of a white solid product, yield: 80.28%. MS (ESI+): m/z calculated for C 8 H 9 N 3 O 2 S,211.0415；found,212.0424(M+H + ).
Compound 45 (8 g,37.87 mmol) was added to a autoclave, 10% palladium on carbon (4 g,3.76 mmol) was added, dissolved with methanol (100 mL), replaced with nitrogen, hydrogen was introduced to 6MPa, heated to 50 ℃ for 3 hours, the reaction was complete by detection, palladium on carbon was filtered off, the filtrate was concentrated, and column chromatography (dichloromethane: methanol=40:1 to 15:1) afforded the product (7.18 g, black solid, yield: 88.06%).
Compound 46 (6 g,27.87 mmol), 5-bromo-2, 4-dichloropyrimidine (7.62 g,33.44 mmol), potassium carbonate (4.74 g,34.31 mmol) were added to a 250mL round bottom flask, tetrahydrofuran (100 mL) was added, the reaction system was stirred at 60℃after 4 hours, the reaction was checked for completion by TLC, the reaction system was brought to room temperature, 200mL of water was added, extraction was performed with ethyl acetate, the organic phase was concentrated, and column chromatography (dichloromethane: methanol=50:1 to 30:1) gave the product (white solid, yield: 87.26%). MS (ESI) + ):m/z calcd for C 12 H 13 BrClN 5 O 2 S,404.9662；found,443.9273(M+K + )。
5-Nitrosalicylic acid (10 g,54.61 mmol) was dissolved in anhydrous dichloromethane (70 mL) at room temperature, thionyl chloride (30 mL) was slowly added dropwise, the reaction system was placed in an oil bath under reflux for 5 hours, the solvent was concentrated, the acid chloride was dissolved in anhydrous tetrahydrofuran (50 mL) and placed at 0 ℃, 1-acetylpiperazine (7 g,54.61 mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the acid chloride, after 1 hour, the reaction was completed by detection, the reaction system was slowly added to 200mL of water, extracted with ethyl acetate, the organic phase was concentrated, and column chromatography (dichloromethane: methanol=50:1 to 30:1) gave the product (14.66 g, white solid, yield: 91.54%). MS (ESI+); found,294.1135 (m+h+).
Compound 48b (10 g,34.10 mmol), compound 9c (12.45 g,40.92 mmol), potassium carbonate (7.07 g,51.15 mmol) were added to a 500mL round bottom flask, DMF (150 mL) was added to dissolve the starting material, and the reaction system was stirred at 75 ℃, after 10 hours the reaction was detected to be complete, 300mL of water was added, extraction with ethyl acetate was performed, and the organic phase was concentrated, and column chromatography (dichloromethane: methanol=55:1 to 20:1) gave the product (8.39 g, pale yellow oil, yield: 57.83%). MS (ESI+): m/z calculated for C 19 H 27 N 3 O 8 ,425.1798；found,426.1847(M+H + ).
Synthetic method the same as the synthesis of compound 35c, starting from compound 49b (7 g,16.45 mmol), was subjected to column chromatography (dichloromethane: methanol=50:1 to 30:1) to give the product (black solid, yield: 80%). MS (ESI) + ):m/z calcd for C 19 H 29 N 3 O 6 ,395.2056；found,418.2138(M+Na + ).
Compound 47 (1 g,2.46 mmol), 50b (1.07 g,2.71 mmol), p-toluenesulfonic acid monohydrate (186.4 mg,0.98 mmol) were added to a 100mL three-necked flask, nitrogen was replaced, isopropyl alcohol (20 mL) was added, the reaction system was left to react at 90 c, after 12 hours, the starting materials were detected to be complete by TLC, the reaction system was left to room temperature, the reaction solution was poured into 100mL of water, extraction was performed with ethyl acetate, the organic phase was concentrated, and column chromatography (dichloromethane: methanol=40:1 to 15:1) gave the product (1.15 g,white solid, yield: 60.98%). 1H NMR (600 MHz, methanol-d 4) delta 8.44 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.38 (d, J=19.6 Hz, 2H), 7.22 (s, 1H), 6.95 (s, 1H), 4.18 (s, 1H), 4.10 (s, 1H), 3.80 (d, J=15.4 Hz, 3H), 3.63 (m, 12H), 3.52 (s, 4H), 3.41 (s, 1H), 3.21 (s, 3H), 3.11 (s, 3H), 2.11 (d, J=33.8 Hz, 3H): MS (ESI+) m/z calcd for C 31 H 41 BrN 8 O 8 S,764.1951；found,418.2138(M+H+).
Compound LY-48 (500 mg,0.65 mmol) was dissolved in anhydrous dichloromethane (10 mL) under ice bath, triethylamine (197.3 mg,1.95 mmol) was added, stirred under ice bath for 0.5 hours, then a dichloromethane solution (10 mL) of p-toluenesulfonyl chloride (247.8 mg,1.3 mmol) was slowly added dropwise, after the addition was completed, the reaction system was left at room temperature for 20 hours, the solvent was removed by rotary evaporation, and column chromatography (dichloromethane: methanol=50:1 to 25:1) gave the product (358.7 mg, white solid, yield: 60%). MS (ESI+): m/z calculated for C 38 H 47 BrN 8 O 10 S 2 ,918.2040；found,919.2125(M+H+).
Compound LY-50 (100 mg,0.11 mmol) was dissolved in 2mL of tetrahydrofuran, 1M tetrahydrofuran solution of tetrabutylammonium fluoride (0.17 mL,0.17 mmol) was added, then refluxed, after 2 hours the reaction was complete by TLC detection, 5mL of water was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, column chromatographed (dichloromethane: methanol=50:1 to 25:1) to 59mg of a white solid, yield: 72.72%.1H NMR (600 MHz, DMSO-d 6) delta 9.03 (s, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 6.77 (s, 1H), 4.70 (s, 2H), 4.49 (s, 1H), 4.41 (s, 1H), 3.99 (s, 2H), 3.66 (s, 2H), 3.60 (s, 1H), 3.52 (m, 7H), 3.41 (d, J=29.7 Hz, 3H), 3.31 (d, J=14.7 Hz, 1H), 3.15 (s, 3H), 3.12 (m, 3H), 3.01 (d, J=36.9 Hz, 2H), 1.96 (d, J=35.3 Hz, 3H).13C NMR(151MHz,DMSO-D6)δ168.84,167.01,166.93,158.96,158.75,156.64,152.83,149.03,147.92,138.17,134.58,125.98,124.62,121.21,119.17,112.94,84.08,82.98,70.41,70.32,70.26,70.14,69.54,68.36,37.82,36.61,25.56,21.72,19.91,14.04.MS(ESI+):m/z calcd for C 31 H 40 BrFN 8 O 7 S,766.1908；found,767.1995(M+H+).
Example 26
5-Nitrosalicylic acid (10 g,54.61 mmol) was dissolved in anhydrous dichloromethane (70 mL) at room temperature, thionyl chloride (30 mL) was slowly added dropwise, the reaction system was placed in an oil bath under reflux for 5 hours, the solvent was concentrated, the acid chloride was dissolved with anhydrous tetrahydrofuran (50 mL) and placed under stirring at 0 ℃, morpholine (4.76 g,54.61 mmol) was dissolved in tetrahydrofuran (50 mL) and slowly added dropwise to the acid chloride, after 1 hour, the reaction was completed by detection, the reaction system was slowly added to 200mL of water, extracted with ethyl acetate, and the organic phase was concentrated, and column chromatography (dichloromethane: methanol=50:1 to 30:1) gave the product (white solid, yield: 90.2%).
The synthesis procedure was the same as that for compound 49b, starting from compound 48b, and subjecting it to column chromatography (dichloromethane: methanol=50:1 to 25:1) to give the product (yellow solid, yield: 56.2%). MS (ESI) + ):m/z calcd for C 17 H 24 N 2 O 8 ,384.1533；found,385.1478(M+H + ).
Compound 49a (1 g,2.6 mmol) was added to a 100 mL round bottom flask, methanol (10 mL), 10% palladium on carbon (0.1 g) and hydrogen were replaced, the reaction system was left to stir at room temperature overnight, the reaction was complete by TLC detection, filtration and concentration of the filtrate gave compound 50a, compound 47 (1.06 g,2.6 mmol), p-toluenesulfonic acid monohydrate (197.8 mg,1.04 mmol) was dissolved in isopropanol (20 mL) without purification, and the reaction system was left to react at 90 ℃ overnight, after the starting material reaction was complete, the reaction was allowed to proceed to room temperature, 50mL of water was added, extracted with ethyl acetate, the organic phase was collected, dried, concentrated, column chromatography (dichloromethane: methanol=50:1 to 20:1) to give the product (white solid, two step yield: 62%). 1H NMR (600 MHz, chloroform-D) delta 8.32 (s, 1H), 7.88 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.18 (s, 1H), 6.74 (s, 1H), 6.22 (s, 1H), 4.77 (s, 2H), 4.07 (s, 1H), 3.98 (s, 1H), 3.72 (D, J=21.2 Hz, 3H), 3.62 (D, J=30.7 Hz, 11H), 3.50 (s, 2H), 3.44 (s, 1H), 3.19 (s, 3H), 3.13 (s, 1H), 3.00 (s, 3H) 13C NMR (151MHz, CHLORM-D) delta 167.47,158.45,158.34,155.59,152.82,149.81,148.28,139.68,134.03,133.74,125.75,124.41,122.39,120.39,112.79,93.52,72.84,70.89,70.47,69.73,68.43,66.98,66.76,61.63,47.30,42.23,40.48,37.81,35.67.
Synthetic method the same as the synthesis of compound LY-50 was carried out by column chromatography (dichloromethane: methanol=50:1 to 30:1) starting from compound LY-47 to give compound LY-49 (white solid, yield: 50.1%). 1 H NMR(600MHz,DMSO-d6)δ9.04(s,1H),8.40(s,1H),8.03(s,1H),7.74(s,2H),7.70(d,J＝7.6Hz,1H),7.52(s,1H),7.42(s,2H),7.36(dd,J＝6.0,13.5Hz,2H),7.29(s,1H),6.76(s,1H),4.71(s,2H),4.07(s,2H),3.97(s,2H),3.63(s,2H),3.50(d,J＝28.6Hz,10H),3.43(s,2H),3.35(s,1H),3.00(s,1H),2.36(s,3H). 13 C NMR(151MHz,DMSO-D6)δ166.89,158.96,158.76,156.61,152.84,149.03,147.93,145.40,138.18,134.64,134.57,132.97,130.64,128.54,128.13,125.89,124.61,121.18,119.24,112.93,93.07,70.47,70.38,70.35,70.26,69.53,68.47,68.37,66.69,66.53,47.14,42.09,37.83,36.62,21.60.MS(ESI+):m/z calcd for C 36 H 44 BrN 7 O 10 S 2 ,877.1774；found,878.1841(M+H + ).
Synthetic method the same as the synthesis of compound LY-52, starting from compound LY-49, was obtained by column chromatography (dichloromethane: methanol=50:1 to 25:1) to give 59mg of a white solid, yield: 72.72%. 1 H NMR(600MHz,DMSO-d6)δ9.03(s,1H),8.40(s,1H),8.02(s,1H),7.70(s,1H),7.51(s,1H),7.37(s,1H),7.34(s,1H),7.29(s,1H),6.77(s,1H),4.70(s,2H),4.49(s,1H),4.41(s,1H),3.99(s,2H),3.66(s,2H),3.60(s,1H),3.52(m,7H),3.41(d,J＝29.7Hz,3H),3.31(d,J＝14.7Hz,1H),3.15(s,3H),3.12(m,3H),3.01(d,J＝36.9Hz,2H),1.96(d,J＝35.3Hz,3H). 13 C NMR(151MHz,DMSO-D6)δ168.84,167.01,166.93,158.96,158.75,156.64,152.83,149.03,147.92,138.17,134.58,125.98,124.62,121.21,119.17,112.94,84.08,82.98,70.41,70.32,70.26,70.14,69.54,68.36,37.82,36.61,25.56,21.72,19.91,14.04.MS(ESI+):m/z calcd for C 31 H 40 BrFN 8 O 7 S,766.1908；found,767.1995(M+H + ).
The testing method comprises the following steps:
this test uses the homogeneous time resolved fluorescence conjugated energy transfer (method) from Cisbio corporation for activity detection. FAK kinase was purchased from ca rna company; the detection kit is purchased from Cisbio; assay plates and multifunctional microplate readers were purchased from Perkin Elmer. In the assay plate, the enzyme, biotin-labeled polypeptide substrate, ATP, and the detection compound are mixed and incubated for reaction. The total concentration of the compounds was 11, and the final system concentration was from 10. Mu.M to 0.17nM. Incubation was performed with 10. Mu.L of 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) for 90 minutes at 23 ℃. mu.L of stop solution (20mM EDTA,0.67nM TK antibody, 50nM XL-665) was added and incubated at 23℃for 60 minutes, envision reading. Calculating the inhibition rate of the compound from the data read by the instrument, and then calculating IC by using mode 205 in XLFIT5 of IDBS 50 The values and specific results are shown in Table 1.
Example 27
Marking a route:
/>
a solution of Kryptofix-2.2.2. (13 mg) in anhydrous acetonitrile (0.7 mL) was used with K 2 CO 3 A mixture of (1 mg) of aqueous (0.3 mL) solution will be captured on the QMA column 18 F - Eluting into a reaction bottle, and drying the solvent in the reaction bottle by nitrogen flow at the temperature of 100 ℃. Then azeotropically dehydrated with 0.5mL of anhydrous acetonitrile, repeated 3 times. A solution of the labeled precursor compound LY-9 (1.5 mg) in anhydrous DMSO (0.3 mL) was rapidly added to the above-mentioned flask, and the flask was sealed and reacted at 95℃for 20min. After the reaction was completed, distilled water (10 mL) was added to quench the reaction, the reaction solution was sucked by a syringe through a Sep-Pak C18 solid phase extraction column activated in advance, and then the reaction product was rinsed off the C18 column with 1mL of acetonitrile, and the rinse solution was collected. The reaction mixture was purified by radio-HPLC (wavelength 254nm, C18 reverse phase semi-preparative column Agela Technologies,5 μm,10×250mm，MeOH:H 2 o=2.8:1.2, flow rate 4 mL/min) liquid phase separation of the product. The liquid phase retention time of the radiopharmaceutical was 21 minutes, and the accuracy, the labeling rate 15% and the radiochemical purity greater than 95% were confirmed by liquid phase co-injection analysis of the same compound LY-10.
The remaining compounds of the invention in Table 1 below were also labeled in a similar manner, with specific labeling rates as shown in Table 1.
TABLE 1 in vitro FAK enzyme Activity inhibition assay results for Standard Compounds
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2. The FAK inhibitor has the advantages of combined medication, and better results can be obtained in the treatment of lung cancer, liver cancer, ovarian cancer, pancreatic cancer, colon cancer, prostate cancer, glioma and the like but not limited to the cancers through the combination with different medicaments, for example, the FAK inhibitor can be combined with erlotinib, crizotinib, emtrictinib, vandetanib, dabrafenib and lartinib for the treatment of lung cancer; such as may be used in combination with paclitaxel or carboplatin for the treatment of ovarian cancer; for example, gemcitabine, capecitabine, pamil mab, paclitaxel, and the like can be used for the treatment of pancreatic cancer; for example, the combination of taxol, platinum drugs and the like can be used for treating esophageal cancer and the like, but is not limited to the combination modes, and the combination modes all show better tumor inhibiting effect than single administration. For example, the tumor inhibiting effect of the compound LY-21 in the A549 xenograft model is shown in the figures 1 and 2, and the compound LY-21 combined with erlotinib can be seen to show better tumor inhibiting effect in a lung cancer mouse model than single administration, and the mice are also good in activity degree, not reduced in weight, and small in toxicity, and can achieve the effect of 1+1 being more than 2. Thus, the FAK inhibitor has very important significance in the aspect of combined administration.
The FAK inhibitor of the invention has advantages in single administration, including but not limited to lung cancer, liver cancer, ovarian cancer, pancreatic cancer, colon cancer, prostate cancer, glioma and the like. For example, the tumor inhibiting effect of the compound LY-3 in the A549 xenograft model is shown in the figures 3 and 4, and it can be seen that the compound LY-3 in the A549 xenograft model is superior to the FAK clinical drug VS-6063 in terms of single administration, and is superior to the current lung cancer treatment drug erlotinib on the market, and the single administration effect is good.
The FAK inhibitor has the advantage of increasing the radiodiagnosis, taking the compound LY-10 as an example, the imaging diagram in an A549 tumor model is shown in figure 5, so that the marked FAK inhibitor can be clearly seen to have higher uptake at the tumor part, can clearly distinguish target from non-target parts, and has better retention at the tumor part 1.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, or alternatives falling within the spirit and principles of the invention.

Claims (5)

1. A focal adhesion kinase-targeting compound, wherein the focal adhesion kinase-targeting compound is selected from the group consisting of:
；
I-I
The R is 4 Selected from hydrogen; the R is 3 Selected from alkyl-substituted alkoxy groups, wherein the alkyl-substituted alkoxy groups have the general formula:the method comprises the steps of carrying out a first treatment on the surface of the The R is 11 Selected from F or 18 F, performing the process; and n is selected from 1-3.
2. The focal adhesion kinase-targeting compound of claim 1 wherein the focal adhesion kinase-targeting compound is at least one of the following:
。
3. use of a compound according to any one of claims 1-2 in the manufacture of a medicament for the treatment of a tumor or in the manufacture of a diagnostic imaging agent for a tumor.
4. The use according to claim 3, wherein the tumor is selected from lung cancer, liver cancer, ovarian cancer, pancreatic cancer, colon cancer, prostate cancer, brain glioma.
5. A pharmaceutical composition comprising a compound of any one of claims 1-2.
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