CN111943889B - Bis-aryl amine compound and preparation method and application thereof - Google Patents

Bis-aryl amine compound and preparation method and application thereof Download PDF

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CN111943889B
CN111943889B CN202010721107.0A CN202010721107A CN111943889B CN 111943889 B CN111943889 B CN 111943889B CN 202010721107 A CN202010721107 A CN 202010721107A CN 111943889 B CN111943889 B CN 111943889B
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anhydrous
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CN111943889A (en
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胡来兴
王天琦
周金明
刘永华
吴萌
李鑫
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Institute of Medicinal Biotechnology of CAMS
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

The invention provides a bi-aromatic amine compound and a preparation method and application thereof, wherein the compound has a structure shown in a formula 1, R1Is selected from C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、‑NH2Sulfonyl or aryl; r5Is oneAbove and R5And R2Selected from hydrogen, C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、‑NH2Sulfonyl or aryl; r3Selected from substituted or unsubstituted five-membered or six-membered heterocyclic rings; linker is selected from-SO2NR4‑、‑CONR4‑、‑NR4‑，R4Selected from hydrogen, C1－12Alkyl groups of (a); v, W, X, Y, Z are independently selected from carbon or nitrogen. The biaryl amine compound provided by the invention has the activity of inhibiting androgen receptor.
Figure DDA0002600034140000011

Description

Bis-aryl amine compound and preparation method and application thereof
Technical Field
The invention relates to a compound, in particular to a bi-aromatic amine compound and a preparation method and application thereof.
Background
Prostate cancer (PCa) is one of the most common male malignancies, with worldwide incidence second only to lung cancer, ranking second to all male malignancies and mortality third to total cancer mortality in the developed world. With the change of life style, environment and other factors and the increasing aging degree of the population, the incidence rate of the prostate cancer shows a continuous and rapid increasing trend in the global area. The pathogenesis and treatment techniques for prostate tumors are also gaining increasing attention.
Androgens (androgens), such as androsterone (Testosterone, T), Dihydroandrosterone (DHT), and adrenal androsterone, are important steroid hormones in the human body, and participate in a variety of key physiological functions by binding to Androgen Receptors (ARs) to promote cell differentiation and tissue growth. AR is a 919 amino acid receptor protein encoded by a DNA sequence located on human X chromosome (q11-12) and widely distributed in proliferative and non-proliferative tissues. The AR protein has three domains: n-terminal domain (NTD), DNA Binding Domain (DBD) and Ligand Binding Domain (LBD). Wherein three binding sites of HBP (Hormone binding pocket, HBP), AF2 and BF3 exist on the LBD binding domain. Androgen binds to HBP and activates or inhibits expression of target genes, thereby regulating physiological function of target tissues.
Androgen imbalance causes prostatic hyperplasia or prostatic cancer, hypersexuality, female acne, seborrheic dermatitis, hirsutism, alopecia, etc. The pathogenesis of prostate cancer is related to the abnormal activation of the androgen receptor signaling pathway. Specifically, androgen binds to AR, which is activated and dimerizes to phosphorylate, enters the nucleus, binds to a specific DNA site (ARE), recruits transcription elements such as RNA polymerase, and regulates the transcriptional expression of target genes, such as genes of Prostate Specific Antigen (PSA), TMPRSS2, FKBP5, and the like. This signaling pathway normally promotes differentiation of prostate epithelial cells, while continued activation regulates cell proliferation, survival, etc., leading to tumor formation and progression. Most prostate cancer patients are androgen-dependent, and androgen deprivation therapy is often used in the early stages of treatment, including surgical resection and drug deprivation. Drug castration is currently in wide clinical use, mainly by lowering androgen levels in the body and antagonizing androgen receptors.
Androgen receptor antagonists are the subject drugs currently used to treat prostate cancer. Such drugs can be divided into steroids and non-steroids. Steroidal antiandrogen drugs are represented by cyproterone acetate (CPA), and include megestrol acetate and medroxyprogesterone acetate. Examples of Nonsteroidal antiandrogens (NSAAs) are Hydroxyflutamide (HF), Bicalutamide (BIC) and the second generation enzalutamide (enzalutamide, ENZ), abiraterone and apalutamide (also known as ARN-509). Enzalutamide is marketed at 2012 for the treatment of advanced male castration-resistant prostate cancer that has spread or recurred, breaking through $ 20 billion in both 2015 and 2016 sales. The enzalutamide has the same action target as the first generation of bicalutamide, acts on androgen receptor to antagonize androgen, and has obviously higher curative effect and side effect than the first generation of bicalutamide. However, the use of these antiandrogen drugs is greatly hindered by the drug resistance phenomenon caused by mutation of amino acids at the Hormone Binding Pocket (HBP) site after a period of treatment, because the target of action is not changed.
Therefore, there is an urgent need to develop novel androgen receptor antagonists to circumvent resistance due to amino acid mutation.
Disclosure of Invention
The invention provides a bi-aromatic amine compound which can inhibit an androgen receptor signaling pathway which is abnormally activated so as to play a certain positive role in treating prostatic cancer.
The invention also provides a preparation method of the diaryl amine compound, which has the advantages of simple synthesis line and low cost.
The invention also provides application of the diaryl amine compound in preparation of an androgen receptor antagonist drug.
The invention also provides an androgen receptor antagonist pharmaceutical composition, and the diarylamine compound is an active ingredient.
The invention provides a bi-aromatic amine compound, which has a structure shown in a formula 1:
Figure BDA0002600034120000021
wherein R is1Is selected from C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、-NH2Sulfonyl or aryl;R2selected from hydrogen, C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、-NH2Sulfonyl or aryl; r is3Selected from substituted or unsubstituted five-membered heterocyclic ring or six-membered heterocyclic ring; linker is selected from-SO2NR4-、-CONR4-、-NR4-，R4Selected from hydrogen, C1－12Alkyl groups of (a); r5Is more than one independently selected from hydrogen and C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、-NH2Sulfonyl, aryl; v, W, X, Y, Z are independently selected from carbon or nitrogen.
The parent structure of the biaryl amine compound provided by the invention is formed by respectively linking six-membered aromatic rings through nitrogen-containing Linker groups, and the six-membered aromatic rings can be benzene rings or nitrogen-containing aromatic rings, so that the biaryl amine compound is called as a biaryl amine compound. In each substituent on the aromatic ring, R1At para position of Linker, R2、R3、R5The positional relationship of (A) is not particularly limited.
In the compounds of the present invention, the sulfonyl group is R6SO2-，R6Is selected from C1－12Alkyl groups of (a); the aromatic group is C6-C30Monocyclic or fused-ring aryl of (A), C5-C30The monocyclic heteroaryl or fused ring heteroaryl of (a).
In the definition of the above substituents, C1－12Alkyl of (A) means C1－12Straight chain alkyl (e.g., methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc.), C3－12Branched alkyl (isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, etc.) or C3－12Cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.); c1－6The alkoxy group (C) is a linear alkoxy group or a branched alkoxy group having 1 to 6 carbon atoms, and may be, for example, a methoxy group (-OCH)3) Ethoxy (-OCH)2CH3) N-propoxy (-OCH)2CH2CH3) Iso-propoxy (-OCH (CH)3)2) Etc.; halogen can be-F, -Cl, -Br, -I; c1－3By haloalkyl is meant C substituted by 1-3 halogen atoms1－3Linear or branched alkyl (e.g. -CF)3、-CHF2、-CH2Br、-CH2CH2Cl, etc.).
Compounds according to the invention, R3Is a five-membered heterocyclic ring or a six-membered heterocyclic ring at an appropriate position on the aromatic ring, and may be imidazole, pyrazole, thiazole, pyrrole, oxazole, isoxazole, etc., or the above five-membered heterocyclic ring or six-membered heterocyclic ring may contain a substituent which may be C1－12Alkyl, amino or epoxyhexane of (a); c1－12The alkyl group of (A) may include C1－12Straight chain alkyl (e.g., methyl, ethyl, propyl, allyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, etc.), C3－12Branched alkyl (isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, isohexyl, etc.), C3－12At least one of cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), amino, or cyclohexene oxide, etc. (i.e., the five-or six-membered heterocyclic ring may have more than one of the above substituents), and the substituent may be at any position of the five-or six-membered heterocyclic ring.
Furthermore, R3May be bonded to the six-membered aromatic ring of the parent structure through the carbon or nitrogen constituting the six-membered aromatic ring.
In the bisaromatic amine compounds of the present invention, V, W is attached to the six-membered aromatic ring except for Linker and R1And may also comprise at least one substituent R5That is, in a six-membered ring containing V, W, except Linker and R1In addition, also has R5When R is5Can be 1-4 same or different groups, specifically, taking the carbon bonded with Linker as the 1-position of the six-membered ring as an example, then R1In position 4 of the six-membered ring, R5May be located at the 2,3,5,6 position of the six membered ring, further, R5Independently selected from C1－12Alkyl of (C)1－6Alkoxy, halogen, C1－3Haloalkyl, -CN, -NO2、-NH2Sulfonyl, aryl, and R5The six-membered ring is benzene.
Non-limiting examples of substituents R5May have 1 to 3 substituents at the 2-, 3-and 5-positions, and examples thereof include 3-fluoro-4-methoxy, 2, 4-dimethoxy, 3,4, 5-trimethoxy, 3-trifluoromethyl-4-fluoro, 3-nitro-4-fluoro, 3-amino-4-fluoro, 3-chloro-4-cyano, 3-trifluoromethyl-4-cyano and the like.
The double-aryl amine compound provided by the invention can be a structure shown in a formula 1a,
Figure BDA0002600034120000031
in the formula 1a, M is-SO2-or-CO-, R4Selected from hydrogen or C1－12Alkyl of R4Preferably hydrogen or C1－6Wherein, C1－6Alkyl of (A) means C1－6Straight chain alkyl, C3－6Branched alkyl or C3－6A cycloalkyl group.
The bis-aryl amine compound may also have a structure represented by formula 1b,
Figure BDA0002600034120000032
the definition of each substituent in formula 1b is the same as that of the substituent in formula 1 a.
Furthermore, in the bis-aryl amine compounds of the present invention, R is3Is positioned at para position or meta position of Linker. Wherein R is3Is in contraposition with a Linker, namely the structure shown in the formula 1 c; r is3And a Linker is in a meta position, namely the structure shown in the formula 1 d.
Figure BDA0002600034120000033
In the bis-arylamines of formula 1c and formula 1d, the present invention does not limit R2In position in a six-membered ring.
Further, R3The six-membered ring is pyridine, and R3On the carbon in the meta position to Linker, i.e. formula 1d, one of X, Y, Z is nitrogen and the other two are hydrogen. As a preferred embodiment, the bis-arylamines of the present invention may further have the structure of formula 1e, formula 1f, or formula 1 g.
Figure BDA0002600034120000034
Figure BDA0002600034120000041
In the bi-aromatic amine compound, two hexahydric aromatic rings bonded with a Linker can be nitrogen-containing aromatic rings of benzene rings at the same time; or one of the six-membered aromatic rings is a benzene ring and the other is a nitrogen-containing aromatic ring, i.e. R1The six-membered aromatic ring can be a benzene ring, R3The six-membered aromatic ring is a nitrogen-containing aromatic ring; or, R1The six-membered aromatic ring may be a nitrogen-containing aromatic ring, R3The six-membered aromatic ring is a benzene ring.
In a specific compound, R1The six-membered ring is a benzene ring, R3The six-membered ring used herein is a nitrogen-containing aromatic ring, and the nitrogen-containing aromatic ring may be, for example, pyridine (one of X, Y, Z is nitrogen), a pyrimidine ring (X, Z is nitrogen) or a pyridazine ring (X, Y is nitrogen, or Y, Z is nitrogen).
By way of non-limiting example, the bis-arylamines of the invention may be, for example, compounds numbered 1 to 42:
Figure BDA0002600034120000042
Figure BDA0002600034120000051
Figure BDA0002600034120000061
the invention also provides a preparation method of the diaryl amine compound, which comprises the following steps:
subjecting a compound represented by formula 2 and a compound represented by formula 3 to a condensation reaction to produce a compound represented by formula 1,
Figure BDA0002600034120000062
wherein L is1And L2Is independently selected from-NHR4One of, -MCl and halogen, M being-SO2-or-CO-to effect a condensation reaction between two six-membered aromatic rings bound by Linker.
In a particular preparation process, L1is-NHR4，L2Is one of-MCl and halogen; or, L1is-MCl or halogen, L2is-NHR4。
Specifically, when the Linker is prepared into-SO2NR4When the compound represented by the formula 1 of (A) is used, L1And L2Is independently selected from-NHR4One of, -MCl and both of which are different from each other, M is-SO2-; when the Linker is prepared as-CONR4When the compound represented by the formula 1 of (A) is used, L1And L2Is independently selected from-NHR4-MCl, M being-CO-, and both being different from each other; when the Linker is prepared to be-NR4When the compound represented by the formula 1 is (A), L1And L2Is independently selected from-NHR4And a halogen different from each other.
The reaction can be carried out in a suitable condensation system, and can be controlled by using a conventional condensation agent and corresponding conditions to obtain the expected product. For example, the compound represented by formula 1a can be prepared in the following manner,
Figure BDA0002600034120000071
the substance of the above reaction is an amidation reaction of the compound represented by formula 2a with the compound represented by formula 3a, and thus the desired product can be obtained by employing the conventional amidation reaction conditions.
For example, the above synthetic route process a may be specifically: dissolving amine compound shown in formula 2a in DMF under anhydrous condition, and adding anhydrous K2CO3Under the condition of ice-water bath (0 ℃), adding the corresponding acyl chloride compound shown in the formula 3a into the solution, reacting at 0-4 ℃ for 30min, then converting to room temperature reaction, and stopping the reaction until the amine compound shown in the formula 2a disappears by monitoring TLC. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography to obtain the compound shown in formula 1 a. Wherein, the compound shown in the formula 2a, the compound shown in the formula 3a and K2CO3In a molar ratio of 1: (1.2-2):1.5, and the eluent for column chromatography is (PE/EA is 1.5/1V/V).
The process a of the above synthetic route can also be specifically as follows: dissolving the amine compound represented by the formula 2a in dry pyridine under anhydrous conditions, adding the acid chloride compound represented by the formula 3a into the reaction solution under ice-water bath conditions (0 ℃), reacting at room temperature until the amine compound represented by the formula 2a disappears as monitored by TLC, and stopping the reaction. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and washing with anhydrous Na2SO4Drying, and according to actual conditions, carrying out column layer separation or crystallization purification to obtain the compound shown in the formula 1 a. Wherein the molar ratio of the compound shown in the formula 2a to the compound shown in the formula 3a is 1: (1.2-2), the eluent for column chromatography is (PE/EA is 1.5/1V/V).
In general, the compound represented by the above formula 2a may be commercially obtained, or may be prepared by the following method.
Specifically, the compounds represented by the formula 2b and the formula 2c react to produce the compound represented by the formula 2a,
Figure BDA0002600034120000072
wherein R is7Selected from halogens, preferably halogen atoms with a weak electronegativity, such as bromine or iodine, PG is selected from the group represented by formula PG1, formula PG2,
Figure BDA0002600034120000073
the synthesis route process b can be specifically as follows: adding the compound shown in formula 2b and the compound shown in formula 2c into a microwave reaction tube, adding dioxane and water to dissolve the raw materials, adding 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl Sphos, K3PO4、Pd2(dba)3And sealing the bottle cap, and then putting the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 90 min. The reaction solution was extracted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (PE/EA 3/1-1/1V/V) to give the compound represented by formula 2 a.
The process b of the above synthetic route can also be specifically: adding the compound shown in formula 2b and the compound shown in formula 2c into a microwave reaction tube, adding DMF and water to dissolve the raw materials, adding K3PO4After bubbling with argon for 15min, Pd (PPh) was added3)4And sealing the bottle cap, and then putting the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 60 min. Extracting the reaction solution with ethyl acetate, sequentially extracting and washing with water and saturated saline, drying with anhydrous sodium sulfate, filtering, and purifying by column Chromatography (CH)2Cl2MeOH 30/1V/V) to give the compound of formula 2 a.
Alternatively, the process b of the above synthetic route may specifically be: adding the compound shown in formula 2b and the compound shown in formula 2c into a microwave reaction tube, adding dioxane and water to dissolve the raw materials, adding K3PO4Argon bubbling for 15min, adding Pd (PPh)3)4And sealing the bottle cap, and then putting the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 90 min. Reaction ofExtracting with ethyl acetate, sequentially extracting with water and saturated brine, washing, drying with anhydrous sodium sulfate, filtering, and purifying by column chromatography (PE/EA is 4/1-2/1V/V) to obtain the compound represented by formula 2 a.
The invention also provides a preparation method of the double-aromatic amine compound, which comprises the following steps:
subjecting a compound represented by formula 4 and a compound represented by formula 5 to a condensation reaction to produce a compound represented by formula 6,
reacting a compound represented by formula 6 with a compound represented by formula 3 to produce a compound represented by formula 1,
Figure BDA0002600034120000081
l above3And L4Is independently selected from-NHR4One of, -MCl and halogen, M being-SO2-or-CO-to effect a condensation reaction between two six-membered aromatic rings bound by a Linker; l is5Selected from halogen, PG is represented by a formula PG1 and a formula PG 2.
Figure BDA0002600034120000082
In the preparation, L3is-NHR4，L4Is one of-MCl and halogen; or, L3is-MCl or halogen, L4is-NHR4。
Specifically, when the Linker is prepared into-SO2NR4When the compound represented by the formula 1 of (A) is used, L3And L4Is independently selected from-NHR4One of, -MCl and both of which are different from each other, M is-SO2-; when the Linker is prepared as-CONR4When the compound represented by the formula 1 is (A), L3And L4Is independently selected from-NHR4-one and different from each other, -MCl, M being-CO-; when the Linker is prepared to be-NR4When the compound represented by the formula 1 is (A), L3And L4Is independently selected from-NHR4One and two of halogen are different from each other。
The above reaction can be carried out in a suitable condensation system, and can be controlled by using a conventional condensation agent and corresponding conditions to obtain the desired product.
In the first condensation reaction, when L3Or L4When it is halogen, L3Or L4Can be mixed with L5Are identical, or L5Is more electronegative than L3Or L4。
The above reaction can be carried out in a suitable condensation system, and can be controlled by using a conventional condensation agent and corresponding conditions to obtain the desired product.
For example, the compound represented by formula 1b can be prepared in the following manner,
Figure BDA0002600034120000091
the above synthetic route process c may specifically be: dissolving the compounds shown in the formulas 5 and 4 in DMF, and adding NaOtBu and (Cypf-tBu) PdCl2And the mixture is heated at 65 ℃ until TLC monitors that the compound shown in the formula 5 is completely reacted, and the reaction is stopped. The solvent was removed under reduced pressure, and the residue was extracted with EtOAC, washed with water and saturated brine sequentially, dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by column chromatography (PE/EA 6/1-10/1V/V) to give the compound represented by formula 6.
The above process d can be the same as the above process b, and the compound represented by formula 6 and the compound represented by formula 7 can be used as raw materials to obtain the compound represented by formula 1d, which is not repeated herein.
The invention also provides application of any one of the amine compounds in preparation of an androgen receptor antagonist drug.
The inventors have studied the bis-aryl amine compound having the structure of formula 1, and surprisingly found that the compound can inhibit the activity of androgen receptor, the compound 2-4, 7, 10, 11, 15, 23-25, 27, 29, 30, 32-34, 38, 39 has an RLU value of less than 30% and shows a strong inhibition effect on androgen receptor when the concentration is 10 μ M, and the compound numbered 11, 15, 23, 30 and 32 has the androgen receptor inhibiting activity equivalent to that of enzalutamide. In addition, the compounds numbered 23 and 27 not only have good inhibition effect on the transcription activity of AR-F876Ld, but also can overcome the drug resistance problem of enzalutamide caused by 876 amino acid mutation of androgen receptor compared with enzalutamide. Therefore, the bis-aryl amine compound with the structure of formula 1 can be used for preparing androgen receptor antagonist medicines.
The invention also provides an androgen receptor antagonist pharmaceutical composition, which comprises any one of the diaryl amine compounds as an androgen receptor antagonist effective component, and also comprises pharmaceutically acceptable pharmaceutical excipients.
The substituted bisarylamine compounds can be formulated as such or in admixture with pharmaceutically acceptable excipients, diluents and the like, in the form of tablets, capsules, granules, powders or syrups. The above preparation can be prepared by conventional pharmaceutical methods.
The pharmaceutical excipients may be those substances which are used in conventional pharmaceutical processes. Examples of usable pharmaceutical excipients include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol and sorbitol, starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch, cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, acacia, dextran, silicate derivatives such as magnesium aluminum metasilicate, phosphate derivatives such as calcium carbonate, sulfate derivatives such as calcium sulfate and the like), binders (e.g., gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl p-hydroxybenzoate, sodium carboxymethyl cellulose, sodium, acacia, dextran, and the like, Propyl p-hydroxybenzoate and the like), flavoring agents (such as conventional sweeteners, acidulants, perfumes and the like), diluents and solvents for injection (such as water). Ethanol, glycerol, and the like).
The double-aromatic amino compound in the androgen receptor antagonist medicine composition is a unit preparation. The unit preparation is a preparation which meets the requirement of effective components for one-time administration, such as one-unit (injection) injection and the like. The amount of drug required for a patient to administer a dose can conveniently be calculated by multiplying the weight of the patient by the unit weight dose required for a dose administered to the patient. For example, in the process of preparing a medicament, the weight of an adult is generally considered to be 50-70kg, and the dosage can be determined by equivalent dose conversion between unit weight doses of experimental animals and humans. For example, the determination can be made by referring to the guidelines proposed by the drug administration such as FDA and SFDA (Huang-Ji Han, et al, "equivalent dose conversion between animals and humans in pharmacological tests", Chinese clinical pharmacology and therapeutics, 2004 Sep; 9(9): 1069-. In the embodiment of the present invention, the conversion of the human and mouse doses by the body surface area conversion factor of 0.0026 can be used.
The example of the administration mode of the androgen receptor antagonist pharmaceutical composition is as follows: intravenous injection, intraperitoneal injection, gastric lavage, oral administration, etc.
The invention also provides a method for treating androgen imbalance, which can be specifically to administer the androgen receptor antagonist medicine composition containing the bis-aryl amine compound to a patient. By administering an androgen receptor antagonist pharmaceutical composition comprising a bis-aryl amine compound of the present invention to a patient, prostatic hyperplasia or prostatic cancer, hypersensitiveness, female acne, seborrhea, hirsutism, alopecia, etc. due to androgen imbalance can be treated.
The biaryl amine compound provided by the invention has obvious inhibitory activity on androgen receptors, wherein some compounds also have obvious inhibitory activity on prostate cancer cells, and can be used as androgen receptor antagonists to treat prostate cancer. In addition, the double aromatic amine compound has the advantages of simple synthetic route, easily obtained raw materials, lower cost and contribution to industrial implementation.
Drawings
FIG. 1a is a graph of the AR inhibitory activity of compound 23 of the present invention;
FIG. 1b is a graph showing the effect of inventive compound 23 on DAR transcription activity, an amino acid mutation at position 876, expressed in PC-3;
FIG. 2a is a graph of the AR inhibitory activity of compound 27 of the present invention;
FIG. 2b is a graph showing the effect of inventive compound 27 on DAR transcription activity, an amino acid mutation at position 876, expressed in PC-3.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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.
EXAMPLE 1 preparation of Compound 1
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 4-acetylbenzenesulfonyl chloride (164.8mg,0.75mmol) was added to the solution, the reaction was allowed to proceed at 0-4 ℃ for 30min, then the reaction was allowed to proceed at room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared, and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white floccule 1(112.4mg, yield: 52.3%).
Hydrogen nuclear magnetic resonance spectrum of compound 1: (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.88(s,1H),10.49(s,1H),8.08(d,J＝7.0Hz,2H),7.91(d,J＝6.5Hz,2H),7.76(s,1H),7.61(s,1H),7.45(s,1H),7.25(s,1H),7.03(d,J＝6.0Hz,1H),6.58(s,1H),2.57(s,3H)；
HRMS calcd for C17H16O3N3S[M+H]+342.09069；Found 342.09061.
EXAMPLE 2 preparation of Compound 2
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 4-fluorobenzenesulfonyl chloride (146.9mg,0.75mmol) was added to the solution, the reaction was carried out at 0-4 ℃ for 30min, then the reaction was switched to room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 2(140.3mg, yield: 70.2%).
Hydrogen nuclear magnetic resonance spectrum of compound 2: (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.88(s,1H),10.32(s,1H),7.83(t,J＝5.5Hz,2H),7.76(s,1H),7.59(s,1H),7.46(d,J＝7.5Hz,1H),7.39(t,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,1H),7.01(d,J＝7.5Hz,1H),6.58(s,1H)；
HRMS calcd for C15H13O2N3FS[M+H]+318.07070；Found 318.07101.
EXAMPLE 3 preparation of Compound 3
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 4-chlorobenzenesulfonyl chloride (159.3mg,0.75mmol) was added to the solution, the reaction was carried out at 0-4 ℃ for 30min, then the reaction was switched to room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE)EA ═ 1.5/1V/V) gave white floc 3(118.5mg, yield: 56.4%).
Hydrogen nuclear magnetic resonance spectrum of compound 3: (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.89(s,1H),10.39(s,1H),7.77(s,1H),7.76(s,2H),7.63(d,J＝8.5Hz,2H),7.59(s,1H),7.46(d,J＝7.0Hz,1H),7.26(t,J＝7.0Hz,1H),7.01(d,J＝7.5Hz,1H),6.58(s,1H)；
HRMS calcd for C15H13O2N3ClS[M+H]+334.04115；Found 334.04144.
EXAMPLE 4 preparation of Compound 4
3- (1H-pyrazol-5-yl) aniline (110.0mg,0.69mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(143.2mg,1.04mmol), under ice-water bath conditions (0 ℃), 4-cyanobenzenesulfonyl chloride (209.2mg,1.04mmol) was added to the solution, the reaction was carried out at 0-4 ℃ for 30min, then the reaction was switched to room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floc 4(170.6mg, yield: 76.3%).
Hydrogen spectrum of compound 4 by nuclear magnetic resonance (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.90(s,1H),10.57(s,1H),8.04(d,J＝7.5Hz,2H),7.92(d,J＝6.5Hz,2H),7.76(s,1H),7.59(s,1H),7.48(s,1H),7.27(s,1H),7.01(d,J＝6.5Hz,1H),6.59(s,1H)；
HRMS calcd for C16H13O2N4S[M+H]+325.07537；Found 325.07426.
EXAMPLE 5 preparation of Compound 5
3- (1H-pyrazol-5-yl) aniline (200.0mg,1.26mmol) was dissolved in anhydrous DMF (7.0mL) under anhydrous conditions, and addedAnhydrous K2CO3(260.4mg,1.89mmol), adding 4-nitrobenzenesulfonyl chloride (418.2mg,1.89mmol) to the solution under the condition of ice-water bath (0 ℃), reacting at 0-4 ℃ for 30min, then changing to room temperature, reacting for 6-8H, and stopping the reaction by TLC (thin layer chromatography) showing that 3- (1H-pyrazol-5-yl) aniline disappears. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floc 5(309.1mg, yield: 71.3%).
Hydrogen nuclear magnetic resonance spectrum of compound 5(1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.89(s,1H),10.64(s,1H),8.37(d,J＝8.5Hz,2H),8.02(d,J＝8.0Hz,2H),7.76(s,1H),7.61(s,1H),7.49(d,J＝7.0Hz,1H),7.27(t,J＝7.5Hz,1H),7.04(d,J＝7.0Hz,1H),6.60(s,1H)；
HRMS calcdfor C15H13O4N4S[M+H]+345.06520；Found 345.06390.
EXAMPLE 6 preparation of Compound 6
Compound 5(90.0mg,0.26mmol) was added to a methanol solvent (25.0mL), Pd/C (10%, 98.0mg) was added, and then H was purged2(35Psi), room temperature for 2-3h to give a clear oil 6(50.4mg, yield: 61.7%).
Compound 6 by NMR1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,MeOD-d6)δppm 7.64(s,1H),7.47(s,1H),7.45(m,3H),7.24(t,J＝7.5Hz,1H),7.05(d,J＝7.5Hz,1H),6.59(s,1H),6.57(s,2H),5.50(s,1H)；
HRMS calcd for C15H15O2N4S[M+H]+315.09102；Found 315.08978.
EXAMPLE 7 preparation of Compound 7
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in super-dry DMF (5.0mL) under anhydrous conditions, and anhydrous was addedK2CO3(130.2mg,0.94mmol), adding 4-trifluoromethyl benzenesulfonyl chloride (184.6mg,0.75mmol) to the solution under ice-water bath condition (0 ℃), reacting at 0-4 ℃ for 30min, then changing to room temperature, reacting for 6-8H, TLC shows that 3- (1H-pyrazol-5-yl) aniline disappears, and stopping the reaction. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white floc 7(153.1mg, yield: 66.2%).
Hydrogen spectrum of compound 7 by nuclear magnetic resonance (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.89(s,1H),10.55(s,1H),7.96(s,4H),7.76(s,1H),7.60(s,1H),7.48(d,J＝7.0Hz,1H),7.27(t,J＝7.5Hz,1H),7.02(d,J＝7.5Hz,1H),6.58(s,1H)；
HRMS calcd for C16H13O2N3F3S[M+H]+368.06751；Found 368.06818.
EXAMPLE 8 preparation of Compound 8
3- (1H-pyrazol-5-yl) aniline (50.0mg,0.31mmol) was dissolved in super-dry DMF (2.0mL) under anhydrous conditions, and anhydrous K was added2CO3(65.1mg,0.47mmol), under ice-water bath conditions (0 ℃), 4-isopropoxybenzenesulfonyl chloride (88.6mg,0.38mmol) was added to the solution, the reaction was carried out at 0-4 ℃ for 30min, the reaction was switched to room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white floccule 8(73.1mg, yield: 66.0%).
Hydrogen spectrum of compound 8 by nuclear magnetic resonance (1HNMR), carbon nuclear magnetic resonance spectrum (C:)13CNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.87(s,1H),10.15(s,1H),7.76(s,1H),7.67(d,J＝8.0Hz,2H),7.58(s,1H),7.42(s,1H),7.23(s,1H),7.01(d,J＝8.5Hz,3H),6.56(s,1H),4.66(t,J＝7.5Hz,1H),1.23(d,J＝5.5Hz,6H)；
13CNMR(101MHz,DMSO-d6)δppm160.9,149.6,138.4,134.8,130.8,130.0,129.4,129.0,121.0,118.7,116.5,115.5,101.8,70.0,21.7；
HRMS calcdfor C18H20O3N3S[M+H]+358.12199；Found 358.12268.
EXAMPLE 9 preparation of Compound 9
3- (1H-pyrazol-5-yl) aniline (113.0mg,0.71mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(196.7mg,1.43mmol), under ice-water bath conditions (0 ℃), 1' -diphenylene-4-sulfonyl chloride (270.1mg,1.07mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed the disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 9(193.6mg, yield: 72.7%).
Hydrogen nuclear magnetic resonance spectrum of compound 9: (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.88(s,1H),10.39(s,1H),7.85(s,4H),7.75(s,1H),7.69(d,J＝7.0Hz,2H),7.65(s,1H),7.46(m,3H),7.42(d,J＝7.0Hz,1H),7.26(s,1H),7.07(d,J＝7.5Hz,1H),6.58(s,1H)；
HRMS calcd for C21H18O2N3S[M+H]+376.11142；Found 376.11041.
EXAMPLE 10 preparation of Compound 10
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), ice water4-Methoxybenzenesulfonyl chloride (156.0mg,0.75mmol) was added to the solution under bath conditions (0 ℃), the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 10(155.1mg, yield: 74.8%).
Compound 10 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.87(s,1H),10.16(s,1H),7.76(s,1H),7.71(d,J＝8.5Hz,2H),7.59(s,1H),7.42(d,J＝7.0Hz,1H),7.23(t,J＝7.5Hz,1H),7.05(d,J＝8.5Hz,2H),7.01(d,J＝8.0Hz,1H),6.57(s,1H),3.77(s,3H)；
HRMS calcd for C16H16O3N3S[M+H]+330.09069；Found 330.09143.
EXAMPLE 11 preparation of Compound 11
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous dichloromethane (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 3-fluoro-4-methoxybenzenesulfonyl chloride (169.5mg,0.75mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentration and column chromatography (DCM/MeOH 45/1V/V) gave white floc 11(70.9mg, yield: 32.4%).
Compound 11 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.89(s,1H),10.28(s,1H),7.73(s,1H),7.57(m,3H),7.45(d,J＝7.5Hz,1H),7.28(dt,J＝18.5,8.0Hz,2H),7.02(d,J＝7.5Hz,1H),6.58(s,1H),3.86(s,3H)；
HRMS calcd for C16H15O3N3FS[M+H]+348.08127；Found 348.08170.
EXAMPLE 12 preparation of Compound 12
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), adding 2, 4-dimethoxybenzenesulfonyl chloride (178.6mg,0.75mmol) to the solution under the condition of ice-water bath (0 ℃), reacting at 0-4 ℃ for 30min, then converting to room temperature, reacting for 6-8H, and stopping the reaction by TLC (thin layer chromatography) showing that the 3- (1H-pyrazol-5-yl) aniline disappears. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floc 12(96.2mg, yield: 42.5%).
Hydrogen nuclear magnetic resonance spectrum of compound 12(1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
HNMR(500MHz,DMSO-d6)δppm 12.85(s,1H),9.87(s,1H),7.75(s,1H),7.69(d,J＝8.5Hz,1H),7.58(s,1H),7.36(d,J＝7.0Hz,1H),7.18(t,J＝7.1Hz,1H),6.99(d,J＝8.0Hz,1H),6.62(s,1H),6.56(d,J＝10.0Hz,1H),6.53(s,1H),3.87(s,3H),3.77(s,3H)；
HRMS calcd for C17H18O4N3S[M+H]+360.10125；Found 360.10187.
EXAMPLE 13 preparation of Compound 13
3- (1H-pyrazol-5-yl) aniline (105.0mg,0.66mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(136.7mg,0.99mmol), adding 2,3, 4-trimethoxybenzenesulfonyl chloride (229.0mg,0.86mmol) to the solution under the condition of ice-water bath (0 ℃), reacting at 0-4 ℃ for 30min, then changing to room temperature for reaction, after 6-8H, TLC shows that 3- (1H-pyrazol-5-yl) aniline disappears, and stopping the reaction. Using B as reaction liquidDiluted with ethyl acetate, the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white floc 13(175.4mg, yield: 68.3%).
Compound 13 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.91(s,1H),10.23(s,1H),7.77(s,1H),7.66(s,1H),7.46(d,J＝6.3Hz,1H),7.27(s,1H),7.06(s,3H),6.59(s,1H),3.75(s,6H),3.66(s,3H)；
HRMS calcd for C18H20O5N3S[M+H]+390.11182；Found 390.11027.
EXAMPLE 14 preparation of Compound 14
3- (1H-pyrazol-5-yl) aniline (100.0mg,0.63mmol) was dissolved in anhydrous dichloromethane (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 3-trifluoromethyl-4-fluorobenzenesulfonyl chloride (198.2mg,0.75mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed the disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentration and column chromatography (DCM/MeOH 50/1V/V) gave white floc 14(53.2mg, yield: 21.9%).
Compound 14 by NMR (H) spectroscopy1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.91(s,1H),10.48(s,1H),8.09(d,J＝4.5Hz,2H),7.73(t,J＝9.5Hz,2H),7.57(s,1H),7.51(d,J＝7.5Hz,1H),7.29(t,J＝8.0Hz,1H),7.01(d,J＝7.5Hz,1H),6.59(s,1H)；
HRMS calcd for C16H12O2N3F4S[M+H]+386.05809；Found 386.05847.
EXAMPLE 15 preparation of Compound 15
3- (1H-pyrazol-5-yl) aniline (100.2mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice-water bath conditions (0 ℃), 3-nitro-4-trifluorobenzenesulfonyl chloride (180.8mg,0.75mmol) was added to the solution, the reaction was allowed to proceed at room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed the disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain yellow floccule 15(95.6mg, yield: 41.9%).
Compound 15 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm12.90(s,1H),10.59(s,1H),8.48(d,J＝4.5Hz,1H),8.11(d,J＝6.0Hz,1H),7.78(m,2H),7.61(s,1H),7.51(d,J＝4.5Hz,1H),7.29(s,1H),7.05(d,J＝7.5Hz,1H),6.60(s,1H)；
HRMS calcd for C15H12O4N4FS[M+H]+363.05578；Found 363.05591.
EXAMPLE 16 preparation of Compound 16
Compound 15(50.0mg,0.14mmol) was added to a methanol solvent (15.0mL), Pd/C (10%, 60.0mg) was added, and H was purged2(35Psi), at room temperature for 3-4h, to give 16 as a clear oil (27.6mg, yield: 59.4%).
Compound 16 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,MeOD-d6)δppm 7.64(s,1H),7.48(s,1H),7.47(d,J＝8.0Hz,1H),7.27(d,J＝8.0Hz,1H),7.24(d,J＝6.5Hz,1H),7.07(d,J＝7.5Hz,1H),7.02–6.98(m,2H),6.58(s,1H),5.49(s,1H)；
HRMS calcd for C15H14O2N4FS[M+H]+333.08160；Found 333.08075.
EXAMPLE 17 preparation of Compound 17
3- (1H-pyrazol-5-yl) aniline (107.3mg,0.67mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(139.3mg,1.01mmol), under ice-water bath conditions (0 ℃), 3-chloro-4-cyanobenzene sulfonyl chloride (206.5mg,0.87mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white solid powder 17(202.2mg, yield: 84.3%).
Compound 17 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.93(s,1H),10.68(s,1H),8.18(d,J＝8.0Hz,1H),8.04(s,1H),7.84(d,J＝7.5Hz,1H),7.78(s,1H),7.60(s,1H),7.52(d,J＝6.0Hz,1H),7.30(s,1H),7.03(d,J＝7.5Hz,1H),6.62(s,1H)；
HRMS calcd for C16H12O2N4ClS[M+H]+359.03640.Found 359.03510.
EXAMPLE 18 preparation of Compound 18
3- (1H-pyrazol-5-yl) aniline (100.3mg,0.63mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(130.2mg,0.94mmol), under ice water bath conditions (0 ℃), 3-trifluoromethyl-4-cyanobenzene sulfonyl chloride (220.5mg,0.82mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed disappearance of 3- (1H-pyrazol-5-yl) aniline, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA ═1.5/1V/V) to give white solid powder 18(196.6mg, yield: 79.6%).
Compound 18 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.93(s,1H),10.71(s,1H),8.37(d,J＝7.5Hz,1H),8.21(s,1H),8.18(d,J＝7.5Hz,1H),7.77(s,1H),7.58(s,1H),7.53(d,J＝6.5Hz,1H),7.30(s,1H),7.01(d,J＝7.0Hz,1H),6.60(s,1H)；
HRMS calcd for C17H12O2N4F3S[M+H]+393.06276；Found 393.06146.
EXAMPLE 19 preparation of Compound 19
3- (1H-pyrazol-5-yl) aniline (103.3mg,0.65mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(134.1mg,0.97mmol), under ice-water bath conditions (0 ℃), 6-chloro-pyridine-3-sulfonyl chloride (178.6mg,0.84mmol) was added to the solution, the reaction was switched to room temperature after 30min at 0-4 ℃, and after 6-8H, TLC showed that 3- (1H-pyrazol-5-yl) aniline had disappeared and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Dried, concentrated and purified by column chromatography (PE/EA: 1.5/1V/V) to give white solid powder 19(163.1mg, yield: 75.1%).
Compound 19 by NMR (H) spectrum1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.91(s,1H),10.59(s,1H),8.73(s,1H),8.13(d,J＝7.5Hz,1H),7.77(s,1H),7.74(d,J＝8.5Hz,1H),7.60(s,1H),7.52(d,J＝5.5Hz,1H),7.30(s,1H),7.03(d,J＝7.5Hz,1H),6.61(s,1H)；
HRMS calcd for C14H12O2N4ClS[M+H]+335.03640；Found 335.03543.
EXAMPLE 20 preparation of Compound 20
Under anhydrous condition, 3- (1H-pyrazol-5-yl) is reacted) Aniline (103.3mg,0.65mmol) was dissolved in anhydrous DMF (5.0mL) and anhydrous K was added2CO3(134.1mg,0.97mmol), adding 4-methylcarbamoylbenzenesulfonyl chloride (196.0mg,0.84mmol) to the solution under ice-water bath condition (0 deg.C), reacting at 0-4 deg.C for 30min, then changing to room temperature, reacting for 6-8H, TLC showed disappearance of 3- (1H-pyrazol-5-yl) aniline, and stopping the reaction. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white solid powder 20(169.0mg, yield: 73.0%).
Compound 20 by nuclear magnetic resonance hydrogen spectrum (1HNMR) was characterized as follows:
1HNMR(500MHz,DMSO)δ12.88(s,1H),10.41(s,1H),8.58(s,1H),7.92(d,J＝8.0Hz,2H),7.85(s,2H),7.76(s,1H),7.60(s,1H),7.45(d,J＝6.7Hz,1H),7.25(d,J＝7.3Hz,1H),7.01(d,J＝6.8Hz,1H),6.58(s,1H),2.75(d,J＝4.1Hz,3H).
EXAMPLE 21 preparation of Compound 21
3- (1H-pyrazol-5-yl) aniline (103.3mg,0.65mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(134.1mg,0.97mmol), adding 4-methyl-benzenesulfonyl chloride (160.0mg,0.84mmol) to the solution under ice-water bath condition (0 deg.C), reacting at 0-4 deg.C for 30min, then changing to room temperature, reacting for 6-8H, TLC shows that 3- (1H-pyrazol-5-yl) aniline disappears, and stopping the reaction. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Dried, concentrated, and purified by column chromatography (PE/EA: 1.5/1V/V) to obtain white solid powder 21(172.0mg, yield: 85.0%).
Compound 21 by nuclear magnetic resonance hydrogen spectrum (1HNMR) was characterized as follows:
1HNMR(500MHz,DMSO-d6)δ12.85(s,1H),10.25(s,1H),7.72(s,1H),7.67(d,J＝7.5Hz,2H),7.57(s,1H),7.42(d,J＝7.0Hz,1H),7.33(d,J＝7.5Hz,1H),7.24(m,1H),7.01(d,J＝7.5Hz,1H),6.55(s,1H),2.31(s,3H).
EXAMPLE 22 preparation of Compound 22
3- (1H-pyrazol-4-yl) aniline (103.3mg,0.65mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(134.1mg,0.97mmol), under ice-water bath conditions (0 ℃), 4-methoxy-benzenesulfonyl chloride (173.0mg,0.84mmol) was added to the solution, the reaction was allowed to proceed at 0-4 ℃ for 30min, then the reaction was allowed to proceed at room temperature, and after 6-8H, TLC showed that 3- (1H-pyrazol-4-yl) aniline had disappeared and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white solid powder 22(171.0mg, yield: 80.0%).
Compound 22 by nuclear magnetic resonance hydrogen spectrum (1HNMR) was characterized as follows:
1HNMR(500MHz,DMSO-d6)δ12.85(s,1H),10.25(s,1H),7.72(s,1H),7.67(d,J＝7.5Hz,2H),7.57(s,1H),7.42(d,J＝7.0Hz,1H),7.33(d,J＝7.5Hz,1H),7.24(m,1H),7.01(d,J＝7.5Hz,1H),6.55(s,1H),2.31(s,3H).
EXAMPLE 23 preparation of Compound 23
4- (1H-pyrazol-5-yl) aniline (132.4mg,0.83mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(172.3mg,1.25mmol), adding 4-methoxy-benzenesulfonyl chloride (190.6mg,1.08mmol) to the solution under ice-water bath condition (0 ℃), reacting at 0-4 ℃ for 30min, then changing to room temperature, reacting for 6-8H, TLC shows that 4- (1H-pyrazol-5-yl) aniline disappears, and stopping the reaction. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1/1V/V) to obtain white solid powder 23(192.8mg, yield: 70.6%).
Compound 23 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 12.81(s,1H),10.17(s,1H),7.73(s,1H),7.69(d,J＝5.0Hz,2H),7.65(s,2H),7.10(s,2H),7.05(d,J＝6.5Hz,2H),6.59(s,1H),3.77(s,3H)；
HRMS calcd for C16H16O3N3S[M+H]+330.09069；Found 330.08942.
EXAMPLE 24 preparation of Compound 24
4- (1H-imidazol-1-yl) aniline (105.0mg,0.66mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(136.7mg,0.99mmol), under ice-water bath conditions (0 ℃), 4-methoxy-benzenesulfonyl chloride (177.4mg,0.86mmol) was added to the solution, the reaction was allowed to proceed at 0-4 ℃ for 30min, then the reaction was allowed to proceed to room temperature, and after 6-8H, TLC showed disappearance of 4- (1H-imidazol-1-yl) aniline, and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white solid powder 24(149.6mg, yield: 68.9%).
Compound 24 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 10.35(s,1H),8.13(s,1H),7.71(d,J＝8.0Hz,2H),7.63(s,1H),7.51(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,2H),7.08(s,1H),7.06(s,2H),3.78(s,3H)；
HRMS calcd for C16H16O3N3S[M+H]+330.09069；Found 330.08980.
EXAMPLE 25 preparation of Compound 25
4- (Thiazol-2-yl) aniline (115.0mg,0.65mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(135.1mg,0.98mmol) under ice-water bath conditions (0 deg.C), 4-methoxy-benzenesulfonyl chloride (175.3mg,0.85mmol) was added to the solution, the reaction was allowed to proceed at 0-4 deg.C for 30min and then switched to room temperature, after 6-8h, TLC showed the disappearance of 4- (thiazol-2-yl) aniline, and the reaction was stoppedShould be used. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 25(183.8mg, yield: 81.7%).
Compound 25 by NMR1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 10.52(s,1H),7.85(s,1H),7.81(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,2H),7.71(s,1H),7.21(d,J＝7.5Hz,2H),7.07(d,J＝8.0Hz,2H),3.78(s,3H)；
HRMS calcd for C16H15O3N2S2[M+H]+347.05186；Found 347.05060.
EXAMPLE 26 preparation of Compound 26
4- (isoxazol-5-yl) aniline (160.0mg,1.0mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions and anhydrous K was added2CO3(204.0mg,1.5mmol), under ice-water bath conditions (0 ℃), 4-methoxy-benzenesulfonyl chloride (247.0mg,1.2mmol) was added to the solution, the reaction was allowed to proceed at 0-4 ℃ for 30min, then the reaction was allowed to proceed to room temperature, and after 6-8h, TLC showed the disappearance of 4- (isoxazol-5-yl) aniline, and the reaction was stopped. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 3/1V/V) to obtain white floccule 26(201.0mg, yield: 61.0%).
Compound 26 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and High Resolution Mass Spectrometry (HRMS) were characterized as follows:
1HNMR(500MHz,DMSO-d6)δppm 10.54(s,1H),8.58(s,1H),7.74(s,4H),7.23(s,2H),7.07(s,2H),6.86(s,2H),3.78(s,3H)；
HRMS calcd for C16H15N2O4S[M+H]+331.07450；Found 331.07470.
EXAMPLE 27 preparation of Compound 27
4- (1H-pyrazol-4-yl) aniline (159.0mg,1.0mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(166.0mg,1.2mmol), under ice-water bath conditions (0 ℃), 4-methoxy-benzenesulfonyl chloride (247.0mg,1.2mmol) was added to the solution, the reaction was allowed to proceed at 0-4 ℃ for 30min, then the reaction was allowed to proceed to room temperature, and after 6-8H, TLC showed disappearance of 4- (1H-pyrazol-4-yl) aniline, and the reaction was stopped. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA: 1.5/1V/V) to obtain white floccule 27(223.0mg, yield: 68.0%).
Compound 27 by NMR1HNMR) was characterized as follows:
1H NMR(500MHz,DMSO-d6)δ12.86(s,1H),10.04(s,1H),8.06(s,1H),7.81(s,1H),7.68(d,J＝8.5Hz,2H),7.45(d,J＝8.0Hz,2H),7.05(d,J＝8.5Hz,4H),3.78(s,3H).
EXAMPLE 28 preparation of Compound 28
4- (N-methyl-pyrazol-3-yl) aniline (120.0mg,0.69mmol) was dissolved in anhydrous DMF (5.0mL) under anhydrous conditions, and anhydrous K was added2CO3(190.0mg,1.38mmol), adding 4-methoxy-benzenesulfonyl chloride (186.0mg,1.30mmol) to the solution under ice-water bath condition (0 deg.C), reacting at 0-4 deg.C for 30min, then changing to room temperature, reacting for 6-8h, TLC showed disappearance of 4- (N-methyl-pyrazol-3-yl) aniline, and stopping the reaction. The reaction solution was diluted with ethyl acetate, the aqueous phase was tested with pH paper and with NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floc 28(192.0mg, yield: 56.0%).
Compound 28 by nuclear magnetic resonance hydrogen spectrum (1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 3.78(3H,s),3.91(3H,s),6.45(1H,d,J＝2.0Hz),6.85(2H,d,J＝9.0Hz),6.99(1H,s),7.08(2H,d,J＝9.0Hz),7.34(1H,s),7.63(2H,d,J＝9.0Hz),7.69(2H,d,J＝9.0Hz)；
13CNMR(CDCl3,125Hz)δppm 39.1,55.6,102.8,114.2,122.1,126.5,129.5,136.0,150.8,163.2.
EXAMPLE 29 preparation of Compound 29
Figure BDA0002600034120000191
1. 3-amino-5- (4-aminophenyl) 1H-pyrazole-1-carboxylic acid tert-butyl ester (180.0mg,0.65mmol) was dissolved in anhydrous pyridine (5.0mL) under anhydrous conditions, 4-methoxy-benzenesulfonyl chloride (135.0mg,0.62mmol) was added to the solution under ice-water bath conditions (0 ℃), the mixture was reacted at 0-4 ℃ for 30min and then at room temperature, and the reaction was stopped after 6-8H. The reaction was diluted with ethyl acetate and the aqueous phase was tested with pH paper and NaHCO3Adjusting pH to 9-11 with saturated solution, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, concentrating, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 29-1(125.0mg, yield: 43.0%).
2. Compound 29-1 was dissolved in dichloromethane (3.0mL), trifluoroacetic acid (1.0mL) was added at 0 ℃, stirred for 30min, the solvent was removed under reduced pressure, and column chromatography separation and purification (PE/EA ═ 1.5/1V/V) gave white floccule 29(89.0mg, yield: 92.0%).
Compound 29 by NMR Hydrogen Spectroscopy (1HNMR and NMR carbon Spectroscopy (C:)13CNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 3.78(3H,s),3.91(3H,s),6.45(1H,d,J＝2.0Hz),6.85(2H,d,J＝9.0Hz),6.99(1H,s),7.08(2H,d,J＝9.0Hz),7.34(1H,s),7.63(2H,d,J＝9.0Hz),7.69(2H,d,J＝9.0Hz)；
13CNMR(CDCl3,125Hz)δppm 39.1,55.6,102.8,114.2,122.1,126.5,129.5,136.0,150.8,163.2.
EXAMPLE 30 preparation of Compound 30
Under anhydrous condition, 4- (1H-pyrazole)-3-yl) aniline (159.0mg,1.0mmol) was dissolved in dry pyridine (5.0mL), 4-chloro-benzenesulfonyl chloride (300.0mg,1.0mmol) was added to the reaction solution under ice-water bath conditions (0 deg.C), and the reaction was stopped after 6-8h at room temperature. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, column chromatography separation and purification (PE/EA is 1.5/1V/V) to obtain white floccule 30(289.0mg, yield: 87.0%).
Compound 30 by nuclear magnetic resonance hydrogen spectrum (1HNMR) was characterized as follows:
1HNMR(500MHz,DMSO-d6)δ12.81(s,1H),10.35(s,1H),7.75(d,J＝8.5Hz,2H),7.67(m,2H),7.63(d,J＝8.5Hz,2H),7.11(d,J＝6.5Hz,2H),6.60(s,1H).
EXAMPLE 31 preparation of Compound 31
4- (1H-pyrazol-3-yl) aniline (159.0mg,1.0mmol) was dissolved in dried pyridine (5.0mL) under anhydrous conditions, 3-fluoro-4-methoxy-benzenesulfonyl chloride (224.0mg,1.0mmol) was added to the reaction mixture under ice-water bath conditions (0 ℃ C.), and the reaction was stopped after reacting for 6 to 8 hours at room temperature. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floccule 31(301.0mg, yield: 87.0%).
Compound 31 by nuclear magnetic resonance hydrogen spectroscopy (1HNMR) was characterized as follows:
1H NMR(500MHz,DMSO-d6)δ12.81(s,1H),10.22(s,1H),7.73(s,1H),7.68(s,2H),7.56(s,2H),7.30(s,1H),7.12(s,2H),6.60(s,1H),3.87(s,3H).
EXAMPLE 32 preparation of Compound 32
4- (1H-pyrazol-3-yl) aniline (159.0mg,1.0mmol) was dissolved in dry pyridine (5.0mL) under anhydrous conditions, 3-nitro-4-fluoro-benzenesulfonyl chloride (239.0mg,1.0mmol) was added to the reaction solution under ice-water bath conditions (0 ℃), and the reaction was stopped after 6 to 8 hours at room temperature. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and removing anhydrous Na2SO4Drying, column chromatography separation and purification (PE/EA: 1.5/1V/V) gave yellow floc 31(322.0mg, yield: 89.0%).
Hydrogen nuclear magnetic resonance spectrum of compound 32: (1HNMR) was characterized as follows:
1H NMR(500MHz,DMSO-d6)δ12.80(s,1H),10.22(s,1H),8.28(s,1H),7.74(m,4H),7.62(d,J＝7.0Hz,2H),7.23(s,1H),6.64(s,1H).
EXAMPLE 33 preparation of Compound 33
4-methyl-3- (1H-pyrazol-3-yl) aniline (173.0mg,1.0mmol) was dissolved in dried pyridine (5.0mL) under anhydrous conditions, 3-fluoro-4-methoxy-benzenesulfonyl chloride (224.0mg,1.0mmol) was added to the reaction mixture under ice-water bath conditions (0 ℃), and the reaction was stopped after 6 to 8 hours at room temperature. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and washing with anhydrous Na2SO4Drying, and purifying by column chromatography (PE/EA is 1.5/1V/V) to obtain white floc 33(259.0mg, yield: 72.0%, isomer near 0.3).
Compound 33 by NMR1HNMR and NMR carbon Spectroscopy (C:)13CNMR) was characterized as follows:
1HNMR(DMSO,500MHz)δppm 2.32(3H,s),3.86(3H,s),6.39(1H,s),6.97(1H,d,J＝9.0Hz),7.12(1H,d,J＝9.0Hz),7.30(2H,m),7.55(2H,m),7.78(1H,s),10.10(1H,s),12.92(1H,s)；
13CNMR(DMSO,125Hz)δppm 20.5,56.3,104.4,113.9,114.2,114.3,119.2,124.4,128.9,131.4,135.1,149.7,150.7.
EXAMPLE 34 preparation of Compound 34
4-methoxy-3- (1H-pyrazol-3-yl) aniline (189.0mg,1.0mmol) was dissolved in dried pyridine (5.0mL) under anhydrous conditions, 3-fluoro-4-methoxy-benzenesulfonyl chloride (224.0mg,1.0mmol) was added to the reaction mixture under ice-water bath conditions (0 ℃), and the reaction was stopped after reacting at room temperature for 6 to 8 hours. Diluting the reaction solution with ethyl acetate, washing with water, washing with saturated NaCl solution, and washing with anhydrous Na2SO4Drying, column chromatography separation and purification (PE/EA 1.5/1V/V) to obtain white floc 34(2110mg, yield: 56.0%).
Compound 34 by nuclear magnetic resonance hydrogen spectrum (1HNMR) was characterized as follows:
1HNMR(DMSO,500MHz)δppm 3.78(3H,s),3.86(3H,s),6.67(1H,s),6.97(2H,m),7.30(1H,t,J＝9.0Hz),7.49(2H,m),7.71(1H,d,J＝10.0Hz),9.89(1H,s),12.84(1H,s).
EXAMPLE 35 preparation of Compound 35
Figure BDA0002600034120000201
1. 2-fluoro-4-iodoaniline (237mg,1.0mmol) and Compound A (278mg,1.0mmol) were added to a microwave reaction tube (20mL), dioxane (3mL) and water (0.3mL) were added to dissolve the sample, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (16mg,0.04mmol), K, were added3PO4(424mg,2.0mmol),Pd2(dba)3(18mg,0.02mmol), sealing the bottle cap, putting the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 90min, and stopping the reaction. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA: 3/1-1/1V/V) to give 35-1(223mg, 86%).
Hydrogen nuclear magnetic resonance spectrum of compound 35-1(1HNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 1.54(2H,m),1.56(1H,m),1.57(1H,m),1.60(1H,d,J＝9.0Hz),2.05(1H,m),2.55(1H,m),3.60(1H,t,J＝11.0Hz),3.89(3H,s),4.12(1H,t,J＝7.5Hz),5.17(1H,d,J＝10.0Hz),6.25(1H,s),6.83(1H,d,J＝7.5Hz),7.09(1H,J＝6.5Hz),7.28(1H,s),7.56(1H,s).
2. compound 35-1(261mg,1.0mmol) was dissolved in anhydrous pyridine (5.0mL), 4-methoxy-benzenesulfonyl chloride (207mg,1.0mmol) was added at 0 ℃, reacted at room temperature for 8 hours, the solvent was removed under reduced pressure, the residue was extracted with ethyl acetate, and the mixture was sequentially washed with a hydrochloric acid solution, water and a saturated saline solution, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA ═ 2/1) to give 35-2(350mg, yield: 81%) as a white floc.
Hydrogen nuclear magnetic resonance spectrum of compound 35-2(1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 1.58(2H,m),1.74(1H,m),1.83(1H,d,J＝9.0Hz),2.06(1H,m),2.55(1H,m),3.56(1H,t,J＝11.0Hz),3.84(3H,s),4.11(1H,t,J＝7.5Hz),5.10(1H,d,J＝10.0Hz),6.28(1H,s),6.89(1H,s),6.93(2H,d,J＝9.0Hz),7.22(2H,t,J＝6.5Hz),7.56(1H,s),7.64(1H,t,J＝8.5Hz),7.79(2H,d,J＝8.5Hz)；
13CNMR(CDCl3,100Hz)δppm 23.0,24.9,29.6,55.7,67.7,84.4,106.9,114.4,116.0,116.2,122.3,125.2,128.0,129.5,130.4,139.6,142.4,152.0,154.5,163.6；
3. compound 35-2(200mg, 0.46mmol) is dissolved in absolute ethanol (5mL), HCl/EtOAc solution (1.0M, 1.5mL) is added at 0 ℃, stirring is carried out for 12h until the reaction is complete, the solvent is removed under reduced pressure, CH is added2Cl2White solid appeared, and was filtered to obtain Compound 35(146mg, yield: 92%).
Hydrogen nuclear magnetic resonance spectrum of compound 35-2(1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(DMSO,500MHz)δppm 3.80(3H,s),6.72(1H,s),7.07(2H,d,J＝7.5Hz),7.26(1H,t,J＝8.0Hz),7.56(2H,d,J＝10.0Hz),7.66(2H,d,J＝7.5Hz),7.74(1H,s),10.02(1H,s)；
13CNMR(DMSO-d6,150Hz)δppm 55.7,102.4,112.3,112.4,114.3,121.2,123.4,123.5,126.6,131.5,154.9,156.6,162.5.
EXAMPLE 36 preparation of Compound 36
Figure BDA0002600034120000211
1. 3-chloro-5-nitropyridine (200mg,1.26mmol) and Compound B (155mg,1.39mmol) were added to a microwave reaction tube, DMF (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(535mg,2.52mmol), argon bubbling for 15min, then Pd (PPh) was added3)4(146mg,0.126mmol), sealing the bottle cap, and placing the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 60 min. Extracting the reaction solution with ethyl acetate, sequentially extracting and washing with water and saturated saline, drying with anhydrous sodium sulfate, and purifying by column Chromatography (CH)2Cl2MeOH 30/1V/V) to give compound 36-1(150mg, yield: 63%).
Compound 36-1 by NMR1HNMR) was characterized as follows:
1HNMR(DMSO-d6,500MHz)δppm 7.08(1H,s),7.92(1H,s),8.85(1H,s),9.27(1H,s),9.42(1H,s),13.30(1H,s).
2. dissolve compound 36-1(150mg,0.79mmol) in MeOH/EtOAc (2:1,30mL) and add Pd/C (10%, 25mg), H2Reduction was performed by hydrogenation (20psi) for 2 hours, and the solvent was removed under reduced pressure to give compound 36-2(120mg, yield: 95%).
Compound 36-2 by NMR1HNMR and NMR carbon Spectroscopy (C:)13CNMR) was characterized as follows:
1HNMR(CD3OD,500MHz)δppm 4.92(2H,br s),6.64(1H,s),7.44(1H,s),7.66(1H,s),7.92(1H,s),8.22(1H,s)；
13CNMR(CD3OD,100Hz)δppm 103.6,119.4,129.9,133.0,133.7,135.9,136.3,146.4.
3. compound 36-2(110mg,0.68mmol) is dissolved in anhydrous pyridine (3.0mL), 3-fluoro-4-methoxy-benzenesulfonyl chloride (154mg,0.68mmol) is added at 0 deg.C, the reaction is carried out at room temperature for 8H, the solvent is removed under reduced pressure, and the residue is purified by C18 column (MeOH/H)2O ═ 2% to 95%), yielding white solid 36(75mg, yield: 32%).
Compound 36 by NMR1HNMR and NMR carbon Spectroscopy (C:)13CNMR) was characterized as follows:
1HNMR(CD3OD,500MHz)δppm 3.87(3H,s),6.71(1H,d,J＝3.0Hz),7.17(1H,t,J＝10.0Hz),7.53(2H,m),7.72(1H,s),7.98(1H,s),8.19(1H,d,J＝3.0Hz),8.66(1H,s)；
13CNMR(CD3OD,100Hz)δppm 56.9,103.7,114.3,114.4,115.7,115.9,125.8,126.3,131.4,136.7,141.5,143.3,151.6,153.1,153.2,154.1.
EXAMPLE 37 preparation of Compound 37
Figure BDA0002600034120000221
1. 2-bromo-3-methyl-4-nitropyridine (217mg,1.0mmol) and Compound B (168mg,1.50mmol) were added to a microwave reaction tube, DMF (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(535mg,2.52mmol), argon bubbling for 15min, then Pd (PPh) was added3)4(146mg,0.126mmol), sealing the bottle cap, and placing the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 60 min. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EtOAc ═ 1.5/1) to give compound 37-1(120mg, yield: 59%).
Nuclear magnetic resonance hydrogen spectrum of compound 37-1(1HNMR), carbon nuclear magnetic resonance spectrum (C:)13CNMR) and mass spectral characterization as follows:
1HNMR(DMSO-d6,500MHz)δppm 2.51(3H,s),6.88(1H,s),7.88(1H,s),8.33(1H,s),8.78(1H,s),13.24(1H,s).
13CNMR(DMSO-d6,100Hz)δppm 103.4,111.8,124.3,130.5,149.4,152.6,153.9,154.9.
ESIMS(+)m/z:205.1[M+H]+；
2. dissolve compound 37-1(240mg,1.18mmol) in MeOH/EtOAc (2:1,30mL), add Pd/C (10%, 25mg), H2Reduction was performed by hydrogenation (30psi) for 2 hours, and the solvent was removed under reduced pressure to give compound 37-2(196mg, yield: 95%).
Hydrogen nuclear magnetic resonance spectroscopy (NMR) on Compound 37-21HNMR) and mass spectra were characterized as follows:
1HNMR(CD3OD,500MHz)δppm 2.02(3H,s),5.78(2H,br s),6.62(1H,s),7.17(1H,s),7.68(1H,s),7.90(1H,s),12.77(1H,s).
ESIMS(+)m/z:175.1[M+H]+.
3. dissolving compound 37-2(170mg,0.97mmol) in anhydrous pyridine (3.0mL), adding 4-methoxybenzenesulfonyl chloride (201mg,0.97mmol) at 0 deg.C, reacting at room temperature for 8h, removing the solvent under reduced pressure, and purifying the residue by column chromatography (MeOH/CH)2 Cl 21% -5%) to give white solid 37(283mg, yield: 85%).
Compound 37 by NMR1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(DMSO,500MHz)δppm 3.01(3H,s),3.84(3H,s),5.96(2H,s),6.94(1H,s),7.17(3H,m),7.93(3H,m),8.44(1H,s)；
13CNMR(DMSO,125Hz)δppm 14.0,55.9,104.2,107.7,115.2,116.8,127.5,130.0,133.4,147.5,149.2,153.1,157.5,164.2.
EXAMPLE 38 preparation of Compound 38
Figure BDA0002600034120000231
1. 2-amino-3-chloro-4-iodo-pyridine (250mg,1.0mmol) and Compound B (123mg,1.10mmol) were added to a microwave reaction tube, DMF (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(535mg,2.52mmol), argon bubbling for 15min, then Pd (PPh) was added3)4(146mg,0.126mmol), sealing the bottle cap, and placing the bottle cap into a microwave reactor for reaction at the temperature of 100 ℃ for 60 min. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EtOAc: 1/1) to give compound 38-1(78mg, yield: 40%).
Hydrogen nuclear magnetic resonance spectroscopy (NMR) on Compound 38-11HNMR) and mass spectra were characterized as follows:
1HNMR(DMSO-d6,500MHz)δppm 6.28(1H,s),6.84(1H,s),6.98(1H,s),7.86(1H,s),13.20(1H,s).
ESIMS(+)m/z:195.0[M+H]+
2. dissolving compound 38-1(78mg,0.40mmol) in anhydrous pyridine (2.0mL), adding 3-fluoro-4-methoxybenzenesulfonyl chloride (90mg,0.40mmol) at 0 deg.C, reacting at room temperature for 8h, removing the solvent under reduced pressure, and purifying the residue by column chromatography (MeOH/CH)2 Cl 21% -5%) to give white solid 38(40mg, yield: 26%).
Hydrogen nuclear magnetic resonance spectrum of compound 38: (1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 3.95(3H,s),5.04(2H,s),6.94(1H,s),7.04(1H,s),7.07(1H,d,J＝8.0Hz),7.76(1H,d,J＝10.0Hz),7.86(1H,d,J＝8.0Hz),7.98(1H,s),8.14(1H,s)；
13CNMR(CDCl3,100Hz)δppm 56.7,110.0,110.2,112.9,113.1,113.2,115.1,126.2,126.3,128.1,128.2,131.4,146.0,150.4,152.9,155.8.
EXAMPLE 39 preparation of Compound 39
Dissolving compound 38-1(78mg,0.40mmol) in anhydrous pyridine (2.0mL), adding 4-methoxybenzenesulfonyl chloride (83mg,0.40mmol) at 0 deg.C, reacting at room temperature for 8h, removing the solvent under reduced pressure, and purifying the residue by column chromatography (MeOH/CH)2 Cl 21% -5%) to give white solid 39(30mg, yield: 21%).
Compound 39 by NMR1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(DMSO,500MHz)δppm 3.85(3H,s),6.45(2H,s),6.76(1H,d,J＝5.0Hz),7.03(1H,s),7.18(2H,d,J＝9.0Hz),7.93(1H,d,J＝5.0Hz),7.99(2H,d,J＝9.0Hz),8.56(1H,d,J＝5.0Hz)；
13CNMR(DMSO,125Hz)δppm 56.0,110.2,110.9,112.7,115.2,127.0,130.4,132.8,137.4,146.0,152.6,156.6,164.4
EXAMPLE 40 preparation of Compound 40
Figure BDA0002600034120000232
1. 2-bromo-3-chloro-5-nitropyridine (237mg,1.0mmol) and Compound A (333mg,1.2mmol) were added to a microwave reaction tube, dioxane (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(424mg,2.0mmol), argon bubbling for 15min, Pd (PPh) added3)4(23mg,0.02mmol), sealing the bottle cap, and placing the bottle cap into a microwave reactor for reaction at the temperature of 130 ℃ for 90 min. Extracting the reaction solution with ethyl acetate, and sequentially extracting and washing with water and saturated saline solutionDried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA: 4/1-2/1) to obtain compound 40-1(274mg, yield: 89%).
Hydrogen nuclear magnetic resonance spectroscopy (NMR) on Compound 40-11HNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 1.64(3H,m),1.98(1H,d,J＝13.0Hz),2.07(1H,d,J＝10.5Hz),2.48(1H,m),3.45(1H,t,J＝11.0Hz),4.00(1H,d,J＝11.0Hz),5.04(1H,d,J＝8.5Hz),6.55(1H,s),7.67(1H,s),8.72(1H,s),9.56(1H,s).
2. dissolve compound 40-1(240mg,0.78mmol) in MeOH/EtOAc (2:1,30mL) and add Pd/C (10%, 25mg), H2Reduction was performed by hydrogenation (20psi) for 3 hours, and the solvent was removed under reduced pressure to give compound 40-2(227mg, yield: 93%).
Compound 40-2 was characterized by mass spectrometry as follows:
ESIMS(+)m/z:228.1[M+H]+.
3. compound 40-2(200mg,0.72mmol) was dissolved in anhydrous pyridine (3.0mL), 4-methoxybenzenesulfonyl rate (148mg,0.72mmol) was added at 0 ℃, reaction was performed at room temperature for 8h, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE/EtOAc ═ 3/1) to give 40-3(170mg, yield: 53%) as an oil.
Compound 40-3 by NMR1HNMR) and mass spectra were characterized as follows:
1HNMR(CDCl3,500MHz)δppm 1.56(2H,m),1.71(1H,m),1.83(1H,d,J＝9.0Hz),2.04(1H,m),2.50(1H,m),3.53(1H,t,J＝11.0Hz),3.81(3H,s),4.00(1H,t,J＝7.5Hz),5.08(1H,d,J＝10.0Hz),6.86(2H,d,J＝8.5Hz),7.04(1H,s),7.55(2H,d,J＝8.5Hz),7.72(1H,s),7.99(1H,s),8.68(1H,s).
ESIMS(+)m/z:449.1[M+H]+.
4. dissolve compound 40-3(150mg, 0.34mmol) in absolute ethanol (5mL), add HCl/EtOAc solution (1.0M, 1.5mL) at 0 deg.C, stir for 12h to completion, remove solvent under reduced pressure, add CH2Cl2White solid appeared, and was filtered to obtain Compound 40(110mg, yield: 89%).
Compound 40 by nuclear magnetic resonance hydrogen spectrum (1HNMR and NMR carbon Spectroscopy (C:)13CNMR)The characterization was as follows:
1HNMR(CDCl3,500MHz)δppm 3.81(3H,s),6.84(1H,s),7.09(2H,d,J＝8.5Hz),7.47(2H,d,J＝8.5Hz),7.88(1H,s),7.95(1H,s),8.14(1H,s),11.42(1H,s),13.25(1H,s)；
13CNMR(DMSO,125Hz)δppm 55.8,105.6,114.4,123.1,128.7,129.8,131.4,131.5,139.0,141.6,144.7,145.0,163.9.
EXAMPLE 41 preparation of Compound 41
Figure BDA0002600034120000241
1. 4-methoxyaniline (148mg,1.2mmol) and 1, 4-dibromobenzene (236mg,1.0mmol) were dissolved in DMF (3.0mL) and NaOtBu (144mg,1.5mmol) and (Cypf-tBu) PdCl were added2(10mg,0.01mmol), the mixture was heated at 65 ℃ for 3h until the disappearance of the starting material spot was monitored by TLC. The solvent was removed under reduced pressure, and the residue was extracted with EtOAC, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA: 6/1) to give compound 41-1(78mg, yield: 28%).
Compound 41-1 by NMR1HNMR) and NMR C spectrum (13CNMR) was characterized as follows:
1HNMR(CDCl3,500MHz)δppm 3.80(3H,s),6.76(2H,br s),6.87(2H,d,J＝8.5Hz),7.04(2H,br s),7.28(2H,d,J＝8.5Hz)；
13CNMR(DMSO,125Hz)δppm 55.6,111.0,114.2,117.0,122.7,124.4,132.1,135.0,144.5,155.7.ESIMS(+)m/z:278.0[M+H]+.
2. compound 41-1(152mg,0.55mmol) and Compound A (229mg,0.85mmol) were added to a microwave reaction tube, dioxane (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(234mg,1.1mmol), argon bubbling for 15min, and Pd (PPh) added3)4(13mg,0.01mmol), sealing the bottle cap, and placing the bottle cap into a microwave reactor for reaction at the temperature of 100 ℃ for 60 min. Extracting the reaction solution with ethyl acetate, sequentially extracting and washing with water and saturated saline solution, and drying with anhydrous sodium sulfateDrying and purifying by column chromatography (PE/EA: 4/1-2/1) to obtain compound 41-2(130mg, 68%).
Nuclear magnetic resonance hydrogen spectrum of Compound 41-2(1HNMR), carbon nuclear magnetic resonance spectroscopy (C13CNMR) and mass spectral characterization as follows:
1HNMR(CDCl3,500MHz)δppm 1.53(2H,m),1.75(1H,m),1.85(1H,m),2.07(1H,m),2.57(1H,m),3.60(1H,t,J＝11.0Hz),3.81(3H,s),4.12(1H,d,J＝7.5Hz),5.23(1H,d,J＝10.0Hz),6.25(1H,s),6.91(1H,d,J＝8.0Hz),6.92(2H,br s),7.13(2H,br s),7.34(2H,s),7.58(1H,s)；
13CNMR(DMSO,125Hz)δppm 23.2,24.9,25.0,29.9,55.6,67.9,84.2,105.9,114.8,123.5,130.2,139.6.
ESIMS(+)m/z:350.2[M+H]+.
3. dissolve compound 41-2(130mg, 0.37mmol) in absolute ethanol (2.0mL), add HCl/EtOAc solution (1.0M, 1.0mL) at 0 deg.C, stir for 12h to completion, remove solvent under reduced pressure, add CH2Cl2When a white solid appeared, compound 41(98mg, yield: 98%) was obtained by filtration.
Compound 41 by NMR1HNMR), carbon nuclear magnetic resonance spectrum (C:)13CNMR) and mass spectral characterization as follows:
1HNMR(DMSO,500MHz)δppm 3.72(3H,s),6.77(1H,m),6.90(2H,d,J＝10.5Hz),6.96(2H,d,J＝9.5Hz),7.10(2H,d,J＝9.5Hz),7.68(2H,m),7.95(1H,m)；
13CNMR(DMSO-d6,150Hz)δppm 55.3,101.7,114.7,121.3,127.1,135.2,146.1,154.4.
ESIMS(+)m/z:266.2[M+H]+.
EXAMPLE 42 preparation of Compound 42
Figure BDA0002600034120000251
1. N-methyl-p-anisidine (200mg,1.45mmol) and 1, 4-dibromobenzene (413mg,1.75mmol) were dissolved in DMF (3.0mL) and NaOtBu (209mg,2.17mmol) and (Cypf-tBu) PdCl were added2(11mg,0.014mmol), the mixture was heated at 65 ℃ for 5h until the disappearance of the starting material spot was monitored by TLC. The solvent was removed under reduced pressure, and the residue was extracted with EtOAC, washed with water and saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA ═ 10/1) to give compound 42-1(110mg, yield 26%).
Nuclear magnetic resonance hydrogen spectrum of Compound 42-1(1HNMR), carbon nuclear magnetic resonance spectrum (C:)13CNMR) and mass spectral characterization as follows:
1HNMR(CDCl3,500MHz)δppm 3.21(3H,s),3.81(3H,s),6.62(2H,d,J＝8.5Hz),6.90(2H,d,J＝9.0Hz),7.06(2H,J＝9.0Hz),7.25(2H,d,J＝8.5Hz)；
13CNMR(CDCl3,125Hz)δppm 40.6,55.6,110.1,114.8,116.8,126.8,131.7,141.7,148.9,156.9.
ESIMS(+)m/z:292.0[M+H]+.
2. compound 42-1(190mg,0.65mmol) and Compound A (278mg,0.97mmol) were added to a microwave reaction tube, dioxane (3mL) and water (0.3mL) were added to dissolve the sample, and K was added3PO4(275mg,1.3mmol), argon bubbling for 15min, Pd (PPh) added3)4(15mg,0.013mmol), after the bottle cap is sealed, the mixture is placed into a microwave reactor for reaction at the temperature of 100 ℃ for 60 min. The reaction mixture was extracted with ethyl acetate, washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and purified by column chromatography (PE/EA: 4/1-2/1) to give compound 42-2(170mg, yield: 73%).
Nuclear magnetic resonance hydrogen spectrum of Compound 42-2(1HNMR), carbon nuclear magnetic resonance spectroscopy (C13CNMR) and mass spectral characterization as follows:
1HNMR(CDCl3,500MHz)δppm 1.58(2H,m),1.74(1H,m),1.84(1H,d,J＝13.0Hz),2.06(2H,m),2.58(1H,m),3.30(3H,s),3.60(1H,t,J＝11.0Hz),3.82(3H,s),4.12(1H,d,J＝13.5Hz),5.24(1H,d,J＝9.5Hz),6.23(1H,s),6.80(2H,d,J＝8.5Hz),6.94(2H,d,J＝9.0Hz),7.16(2H,d,J＝9.0Hz),7.33(2H,d,J＝9.0Hz),7.56(1H,s)；
13CNMR(CDCl3,100Hz)δppm 23.0,24.9,29.8,40.3,55.4,67.7,84.0,105.6,114.0,114.9,119.1,127.5,129.6,139.4,141.1,144.5,149.8,157.1.
ESIMS(+)m/z:364.2[M+H]+.
3. dissolve compound 42-2(170mg, 0.46mmol) in absolute ethanol (2.0mL), add HCl/EtOAc solution (1.0M, 1.0mL) at 0 deg.C, stir for 12h to completion, remove solvent under reduced pressure, add CH2Cl2When a white solid appeared, it was filtered to obtain Compound 42(98mg, yield: 98%).
Compound 42 by NMR1HNMR), carbon nuclear magnetic resonance spectroscopy (C13CNMR) and mass spectral characterization as follows:
1HNMR(DMSO,500MHz)δppm 3.72(3H,s),6.77(1H,m),6.90(2H,d,J＝10.5Hz),6.96(2H,d,J＝9.5Hz),7.10(2H,d,J＝9.5Hz),7.68(2H,m),7.95(1H,m)；
13CNMR(DMSO-d6,150Hz)δppm 55.3,101.7,114.7,121.3,127.1,135.2,146.1,154.4.
ESIMS(+)m/z:266.2[M+H]+.
evaluation of biological Activity
1. Dual luciferase reporter gene assays
1.1 cell lines and drugs:
(1) LNCaP cells were purchased from ATCC, CRL-1740;
(2) dihydrotestosterone (DHT) was offered by the university of magenter, canada;
enzalutamide (enzalutamide, ENZ) was a gift from shanghai medicine;
IMB-A6
Figure BDA0002600034120000261
1.2 reagents and instruments
(1) Biochemical reagent: F-12K medium, RPMI1640 medium, Phenol red free RPMI1640 medium, FBS, charcol-strained FBS, 0.25% trypsin containing EDTA, PBS all from GiBCO, USA, FBS charcol-strained carbon adsorption special grade fetal bovine serum from Israel Biological Industries. The kit comprises: dual luciferase Activity assay kit Dual-luciferase assay System was purchased from Promega, USA.
(2) Plasmid: the PSA-Jappan plasmid was complimentary to professor Hiroyuki, Japan cancer chemotherapy center, co-expressing prostate specific antigen and firefly luciferase. The Renilla plasmid is owned by the present immunization room and expresses Renilla luciferase.
(3) The instrument comprises: the microplate reader Centro XS3LB 960 was purchased from Berthold, Germany.
1.3 Experimental methods:
in 24-well plates, inoculate 1.6X 105one/mL LNCaP cell suspension was seeded at 500. mu.L per well. When the cells grow to 80%, 100ng of PSA-luc and 1ng of pCMV-Renilla plasmid are co-transfected into each well, and the culture medium is changed into a phenol red-free RPMI1640 culture medium containing 10% of charcol-strippod FBS 6h after transfection; after 24h of transfection, 1 μ L of DHT and drugs (compound 1-42, positive control enzalutamide, IMB-a6) with corresponding concentrations were added to each well, culture was continued for 24h, DHT was used as a blank control, the medium was aspirated, 100 μ L of 1 × PLB was added to each well to lyse for 20min, cell lysates were collected in a clean EP tube, centrifuged, 20 μ L of supernatant was taken to a clean white 96-well plate, and the fluorescence value was measured with a 960 microplate reader according to Dual-luciferase protocol, and the inhibition of transcription activity of AR by the calibrated luciferase activity (relative fluorescence value, RLU) responsive drugs was shown in table 1, with the lower the RLU value, the stronger the inhibition activity.
TABLE 1
Figure BDA0002600034120000271
Figure BDA0002600034120000281
As can be seen from Table 1: most of the diaryl amine compounds have outstanding anti-AR activity, wherein the anti-AR activity of the compounds 15, 23, 30 and 32 is equivalent to that of enzalutamide, and the diaryl amine compounds can be used as lead compounds of AR antagonists for research.
2. MTT method test for detecting cell proliferation inhibition activity of compound
2.1 materials (1) cells: LNCaP cells were purchased from ATCC, CRL-1740; the cells were cultured in RPMI1640 medium containing 10% FBS. PC-3 cells were donated by McGill university, Canada; the culture was carried out in F-12K medium containing 10% FBS. (2) Biochemical reagents: F-12K, RPMI1640 medium, FBS, charcoal-stripped FBS, 0.25% pancreatin with EDTA, PBS all from GiBCO, USA, FBS charcoal-stripped charcoal-adsorbed special grade fetal bovine serum from Israel Biological Industries.
2.2 Instrument: the microplate readers Centro XS3LB 960 were all purchased from Berthold, Germany.
2.3 Experimental methods: respectively collecting LNCaP and PC-3 cells with good growth, and making into 2 × 104Cell suspension per mL, seeded in 96-well plates at 200 μ L per well. After 24h of culture, 1 μ L of the corresponding drug (the partial diarylamine compound, the positive control enzalutamide, and the IMB-a6) was added to each well, and each group of drugs was divided into three groups in parallel, while a blank group was set. Culturing for 72h, adding 20 μ L MTT solution 5g/L prepared with PBS into each well, culturing for 2-4h, carefully removing supernatant, dissolving precipitate with 100 μ L isopropanol in each well, mixing well on 96-well plate oscillator for 30min, measuring absorbance value with multifunctional microplate reader at 570nm wavelength, and using IC to obtain the final product50The bis-aryl amines of the present invention were further evaluated for their cytotoxic activity and selectivity for AR, and the specific results are shown in table 2.
TABLE 2
Figure BDA0002600034120000282
From table 2, it can be seen that: the bis-aryl amines of the present invention all have certain anti-AR activity, especially IC of compounds 23, 27, 30 and 3250The value is lower than that of enzalutamide, and the compound has stronger AR inhibition activity, so that the compound can be further researched as a lead compound.
3. Can inhibit the activity of mutant hormone receptors
Currently, several series of mutations in key sites of AR are found, including tryptophan (W) → leucine (L) or cysteine (C) at position 741, threonine (T) → alanine (a) at position 877, and phenylalanine (F) → leucine (L) at position 876. Wherein F876L is resistant to enzalutamide.
Will be 1.4X 105one/mL of PC-3 cell suspension was seeded at 500. mu.L/well in 24-well plates. When the cells grew to 80%, 100ng of PSA-luc, 20ng of AR-F876L, and 1ng of pCMV-Renilla plasmid were co-transfected per well. The culture medium is changed into phenol red-free RPMI1640 culture medium containing 10% charcol-stripped FBS 6h after transfection; after 24h of transfection, the culture was continued for 24 h. Finally, the medium was aspirated off, 100. mu.L of 1 XPLB was added to each well for lysis for 20min, the cell lysate was collected in a clean EP tube, centrifuged, and 20. mu.L of the supernatant was taken in a clean white 96 well plate according to Dual-
Figure BDA0002600034120000291
Instructions for the Luciferase assay System kit fluorescence was measured using a Centro XS3LB 960 microplate reader. Three sets of replicates were set up and statistically analyzed, where P<0.05，**P<0.01 is referred to the DHT group. Experimental data on
Figure BDA0002600034120000292
Expressed and plotted using GraphPad Prism 5.0 and statistically analyzed. The results are shown in FIG. 1a, FIG. 1b, FIG. 2a and FIG. 2b (FIG. 1b and FIG. 2b show the addition of 1. mu.L each of the compounds or enzalutamide containing DMSO only, DMSO + DHT and DMSO + DHT + at the corresponding concentrations, respectively).
FIG. 1a is a graph showing the AR inhibitory activity of compound 23 of the present invention, and FIG. 1b is a graph showing the effect of compound 23 of the present invention on DAR transcription activity, which is a mutation at amino acid 876, expressed in PC-3. FIG. 2a is a graph showing the AR inhibitory activity of compound 27 of the present invention, and FIG. 2b is a graph showing the effect of compound 27 of the present invention on DAR transcription activity, which is a mutation at amino acid 876, expressed in PC-3. FIG. 1a, FIG. 1b, FIG. 2a and FIG. 2b show that compounds 23 and 27 also have a very good inhibitory effect on the transcriptional activity of F876L mutant AR, on the transcriptional activity of AR-F876L, and show a dose-dependent relationship；IC501.05. mu.M and 0.16. mu.M, respectively. And the compounds 23 and 27 have a significant inhibiting effect on the transcriptional activity of AR-F876L at 0.8 mu M, and the comparison of the effect results of the compounds with that of enzalutamide shows that 23 and 27 can overcome the drug resistance problem of enzalutamide caused by mutation of the 876 th amino acid of AR, and can possibly solve the drug resistance problem of the enzalutamide androgen receptor antagonist in clinic.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.

Claims (6)

1. A bis-aryl amine compound having the structure of formula 1:
Figure FDA0003644786600000011
wherein, the bis-aryl amine compound with the structure of formula 1 is selected from any one of the following compounds:
Figure FDA0003644786600000012
2. a method for preparing the bis-aryl amine compound of claim 1, comprising the steps of:
carrying out condensation reaction on the compound of the formula 2 and the compound of the formula 3 to generate the compound shown in the formula 1,
Figure FDA0003644786600000013
wherein L is1And L2Is independently selected from-NH2、-SO2One of Cl to realize the bonding of two six-membered aromatic rings by a Linker through a condensation reaction.
3. The method of preparing bis-aryl amines according to claim 2, further comprising the steps of:
reacting the compound of formula 2b with the compound of formula 2c to produce a compound of formula 2a,
Figure FDA0003644786600000021
wherein R is4Selected from hydrogen, R7Is selected from halogen, PG is independently selected from groups shown as a formula PG1 and a formula PG2, and formula 2a is the same as the compound shown as the formula 2;
Figure FDA0003644786600000022
4. a method for preparing the bis-aryl amine compound of claim 1, comprising the steps of:
subjecting a compound represented by formula 4 and a compound represented by formula 5 to a condensation reaction to produce a compound represented by formula 6,
reacting a compound represented by formula 6 with a compound represented by formula 7 to produce a compound represented by formula 1,
Figure FDA0003644786600000023
wherein L is3And L4Independently selected from-NH2One of, -MCl, M is-SO2-, to realize that two hexahydric aromatic rings are linked by Linker through condensation reaction;
L5is selected from halogen, PG is selected from groups shown as a formula PG1 and a formula PG2,
Figure FDA0003644786600000024
5. use of a bis-aryl amine compound according to claim 1 for the preparation of an androgen receptor antagonist drug.
6. An androgen receptor antagonist pharmaceutical composition, which comprises the bis-aryl amine compound of claim 1 as an androgen receptor antagonist effective ingredient, and further comprises pharmaceutically acceptable pharmaceutical excipients.
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