CN113583007A - Pyrrolopyrimidine BTK inhibitor and preparation method and application thereof - Google Patents
Pyrrolopyrimidine BTK inhibitor and preparation method and application thereof Download PDFInfo
- Publication number
- CN113583007A CN113583007A CN202111015697.6A CN202111015697A CN113583007A CN 113583007 A CN113583007 A CN 113583007A CN 202111015697 A CN202111015697 A CN 202111015697A CN 113583007 A CN113583007 A CN 113583007A
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- CN
- China
- Prior art keywords
- phenyl
- methyl
- methylpiperazin
- pyrrolo
- amino
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- 229940124291 BTK inhibitor Drugs 0.000 title abstract description 11
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- 201000010099 disease Diseases 0.000 claims abstract description 13
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- 230000000155 isotopic effect Effects 0.000 claims abstract description 10
- 239000000651 prodrug Substances 0.000 claims abstract description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 10
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- 150000001408 amides Chemical class 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 7
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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Abstract
The invention provides a pyrrolopyrimidine BTK inhibitor and a preparation method and application thereof, belonging to the technical field of biological medicines. The compound has a general structural formula shown in a formula (I):
wherein R is1Selected from different electron withdrawing or donating groups; r2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide; the compounds also include pharmaceutically acceptable salts, stereoisomers, isotopic labels, solvates, polymorphs, or prodrugs thereof. Experiments prove that the compound can effectively inhibit Ramos cell proliferation of high-expression BTK and has low toxicity to normal hPBMC (human platelet-factor receptor-like endothelial cell)The compound is expected to be used for treating rheumatoid arthritis and related diseases, and therefore has good practical application value.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a pyrrolopyrimidine BTK inhibitor, and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Rheumatoid Arthritis (RA) is a common autoimmune disease, and its pathological features are mainly synovitis and cartilage damage, which can seriously cause deformity and other complications, and greatly affect the quality of life of patients. Epidemiological investigations have found that about 4000 million patients are suffering from rheumatoid arthritis worldwide, and china accounts for about one seventh of them.
At present, the pathogenesis of rheumatoid arthritis is not clear, and may be related to factors such as genes, heredity, environment, posttranslational modification and the like. Under the influence of these Factors, anti-Citrullinated peptide antibodies (ACPA) can bind to Citrullinated antigens to form immune complexes, and then bind to Rheumatoid Factors (RF), which cause massive complement activation, which can cause immune system intolerance, resulting in asymptomatic synovial inflammation, which further causes cartilage damage and joint destruction; the destruction of the tissue in turn leads to the release of additional autoantigens, further exacerbating the disease.
Drug therapy remains the primary mode of treatment for this disease, unless steroidal anti-inflammatory drugs, glucocorticoids, and traditional synthetic disease-modifying antirheumatic drugs are used, biologics and protein tyrosine kinase inhibitors have become more widely used in recent years due to their higher clinical remission rates; however, most biological agents are expensive and inconvenient to use, and the development of new small-molecule tyrosine kinase inhibitors is a potential clinical need. Currently, small molecule tyrosine Kinase inhibitors for RA mainly include JAK (janus Kinase) inhibitors and Bruton's Tyrosine Kinase (BTK) inhibitors, 8 JAK inhibitors are currently on the market, but no BTK inhibitor for rheumatoid arthritis is already on the market.
Bruton's tyrosine kinase is a member of the Tec family of non-receptor tyrosine kinases, plays a key role in B cell and myeloid cell signaling pathways, inhibits over-activation of BTK to reduce cytokine secretion and autoantibody production, and helps to alleviate the symptoms of rheumatoid arthritis. No BTK inhibitor aiming at RA is on the market at present, so that the development of a novel BTK inhibitor has important significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a pyrrolopyrimidine BTK inhibitor and a preparation method and application thereof. A series of non-covalent pyrrolopyrimidine compounds are designed and synthesized, and experiments prove that the compounds can effectively inhibit Ramos cell proliferation of high-expression BTK and have low toxicity to normal hBMC cells, so that the compounds are expected to be used for treating rheumatoid arthritis and related autoimmune diseases.
Specifically, the invention relates to the following technical scheme:
in a first aspect of the present invention, there is provided a compound having the general structural formula shown in formula (I):
wherein R is1Selected from different electron withdrawing or donating groups; r2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide;
further, R1Is any one of 4-methyl, 4-ethyl, 4-trifluoromethyl, 4-isopropyl, 4-cyclopropyl, 4-methoxy, 4-tert-butyl, 4-dimethylamino, 4-cyano, 2, 4-dimethyl, 3-trifluoromethyl and 2-fluoro-4-trifluoromethyl;
the compounds also include pharmaceutically acceptable salts, stereoisomers, isotopic labels, solvates, polymorphs, or prodrugs thereof.
Further, the structure of the compound can be further represented by formula (II):
wherein, R is2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide.
In a second aspect of the present invention, there is provided a process for the preparation of the above compound, which comprises:
a) when the compound is a compound shown as a formula (I) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
b) when the compound is a compound shown as a formula (II) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
in a third aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as described in the first aspect above.
And a pharmaceutical formulation comprising a compound as described in the first aspect above and at least one pharmaceutically acceptable adjuvant and/or carrier.
In a fourth aspect of the present invention, there is provided a compound as described in the first aspect above or a pharmaceutical composition or pharmaceutical preparation as described in the third aspect above for use in the preparation of a medicament or reagent for inhibiting bruton's tyrosine kinase overexpression.
In a fifth aspect, the present invention provides the use of a compound of the first aspect or a pharmaceutical composition or formulation of the third aspect for the manufacture of a medicament for the treatment of a disease associated with bruton's tyrosine kinase overexpression; preferably, the disease is an autoimmune disease, more preferably rheumatoid arthritis.
In a sixth aspect of the invention, there is provided a method of treating rheumatoid arthritis, comprising administering to a subject a therapeutically effective amount of a compound according to the first aspect of the invention or a pharmaceutical composition or formulation according to the third aspect of the invention.
The beneficial technical effects of one or more technical schemes are as follows:
a series of non-covalent pyrrolopyrimidine BTK inhibitors designed by the technical scheme have novel structures and are not reported in documents. Activity results at cellular level: the proliferation inhibition rate of partial compounds such as W-10, W-8 and W-17 on Ramos cells under the concentration of 10 mu M is obviously higher than that of a positive drug Fenebrutinib, and the level of partial compounds is equivalent to that of the positive drug.
The research of the technical scheme discovers that the activity of the compound is increased when 4-methylpiperazine replaces morpholinyl of a lead compound to be used as a new solvent exposure region, and 7H-pyrrolo [2,3-d ] is introduced into a hinge region]Reduced activity in the pyrimidine nucleus; the subsequent modification of the pocket region of H3 shows that R is the same as R1The group is methyl, ethyl, methoxy, dimethylamino and the like, and has better activity of a smaller electron-donating group, wherein the dimethylamino substitution activity is the best, and the proliferation inhibition rate on Ramos cells is about two times higher; the activity of the sulfonamide compound is superior to that of ester group, amide and the like; with respect to R2Different substitution of the groups has little influence on the activity. In the hBMC cells of normal people, the toxicity of the compound W-10 to normal lymphocytes is lower than that of positive drugs when the concentration of the compound W-10 is within 12 mu M, and the cell viability is maintained to be more than 80%; when the concentration of the compound is increased to 25 mu M or more, the toxicity to normal lymphocytes is increased, and the cell activity is obviously reduced.
In conclusion, the compound in the technical scheme has a good inhibition effect on BTK overexpression, can be used for preventing and treating rheumatoid arthritis and diseases, and therefore has a good practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a graph showing the results of the anti-proliferative activity of the compound of the present invention on Ramos cells, wherein A is the inhibition rate of the compound on Ramos cell proliferation at a concentration of 10. mu.M; b is IC of compound W-1050(ii) a C is IC of positive drug Fenebbrutinib50。
FIG. 2 is a graph showing the comparison of toxicity of compound W-10 of the present invention and Fenebruntinib against hPPBMC.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The present invention is further illustrated by reference to specific examples, which are intended to be illustrative only and not limiting. If the experimental conditions not specified in the examples are specified, they are generally according to the conventional conditions, or according to the conditions recommended by the sales companies; materials, reagents and the like used in examples were commercially available unless otherwise specified.
As mentioned previously, bruton's tyrosine kinase is a member of the Tec family of non-receptor tyrosine kinases that play a key role in B cell and myeloid cell signaling pathways, inhibiting over-activation of BTK reduces cytokine secretion and autoantibody production, contributing to the alleviation of the symptoms of rheumatoid arthritis. No BTK inhibitor aiming at RA is on the market at present, so that the development of a novel BTK inhibitor has important significance.
In view of the above, in one exemplary embodiment of the present invention, there is provided a compound having a general structural formula as shown in formula (I):
wherein R is1Selected from different electron withdrawing or donating groups; r2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide;
further, R1Is any one of 4-methyl, 4-ethyl, 4-trifluoromethyl, 4-isopropyl, 4-cyclopropyl, 4-methoxy, 4-tert-butyl, 4-dimethylamino, 4-cyano, 2, 4-dimethyl, 3-trifluoromethyl and 2-fluoro-4-trifluoromethyl;
the compounds also include pharmaceutically acceptable salts, stereoisomers, isotopic labels, solvates, polymorphs, or prodrugs thereof.
Further, the structure of the compound can be further represented by formula (II):
wherein, R is2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide.
In embodiments of the invention, by way of example, the compounds of the invention may be of the following structure:
4-tert-butyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-3);
4-methyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-4);
4-ethyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-5);
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide (W-6);
4-isopropyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-7);
4-methoxy-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-8);
4-cyclopropyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-9);
4-dimethylamino-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-10);
4-cyano-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-11);
2, 4-dimethyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-12);
2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyridin-2-yl } -N- [4- (trifluoromethyl) phenyl ] benzamide (W-13);
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -3- (trifluoromethyl) benzamide (W-14);
2-fluoro-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide (W-15);
n- { 2-methyl-3- {4- [ (4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzenesulfonamide (W-16);
4- (tert-butyl) -N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzenesulfonamide (W-17);
tert-butyl 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl-4-benzoate (W-18);
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carboxamide (W-19);
n- {3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide (W-20);
n- { 2-fluoro-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide (W-21);
n- { 2-cyano-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide (W-22).
The pyrrolopyrimidine compounds of the present invention may be present in free form or in salt form for the purpose of improving water solubility and increasing bioavailability. "pharmaceutically acceptable salt" refers to conventional non-toxic salts, including inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate salts; organic acid salts such as acetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate and ascorbate; inorganic base salts such as sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt and aluminum salt; and organic base salts such as arginine salt, benzathine salt, choline salt, diethylamine salt, dialcohol amine salt, glycinate salt, lysine salt, meglumine salt, ethanolamine salt, and tromethamine salt. In addition, one skilled in the art may remove one salt and leave another salt aside for solubility, stability, ease of formulation, etc. The determination and optimization of these salts is within the experience of the skilled artisan.
In still another embodiment of the present invention, there is provided a method for preparing the above compound, the method comprising:
a) when the compound is a compound shown as a formula (I) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
b) when the compound is a compound shown as a formula (II) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
wherein,
and a, adding oxalyl chloride and DCM, and reacting for 1-5h at 0-30 ℃.
b, adding DIPEA and DCM to react for 3-8h at 0-20 ℃.
c with the proviso that Pd (dppf) Cl is added2KOAc, bis-pinacolato diboron and dioxane, and reacting for 8-12h at 80-110 ℃.
And d, adding TsCl, TEA, DMAP and DCM, and reacting for 4-8h at 0-30 ℃.
e, adding DIPEA and EtOH, and reacting for 4-8h at 40-80 ℃.
The condition of f is that Pd (OA) is addedC)2、PCy3、Cs2CO3、DMF、H2And O, reacting for 10-30min at 80-140 ℃ in a microwave reactor.
In a further embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound as described in the first aspect above.
And a pharmaceutical formulation comprising a compound as described in the first aspect above and at least one pharmaceutically acceptable adjuvant and/or carrier.
The auxiliary material of the invention refers to the components of the pharmaceutical composition or the pharmaceutical preparation except the effective components, which are nontoxic to the testee. Adjuvants commonly used in the art such as buffers, stabilizers, preservatives or excipients, commonly used excipients such as binders, fillers, wetting agents, disintegrants and the like.
By way of example, optional excipients in the formulations of the present invention include, but are not limited to: the excipient is selected from calcium phosphate, magnesium stearate, talc, dextrin, starch, gelatin cellulose, methyl cellulose, sodium carboxymethyl cellulose and polyvinylpyrrolidone.
The pharmaceutical carrier of the present invention may be a pharmaceutically acceptable solvent, suspension, vesicle, nanomaterial, etc. for delivering the compound of the above first aspect of the present invention into an animal or human. The carrier may be a liquid or solid and is selected according to the intended mode of administration. Proteins and liposomes are also drug carriers.
The compounds of the present invention may be formulated into pharmaceutical compositions or formulations using well known techniques by those skilled in the art. For example, any of the compounds (at least one compound) disclosed in the above first aspect of the present invention may be mixed with a pharmaceutically acceptable excipient, and then, if necessary, the resulting mixture may be formed into a desired shape. The preparation of pharmaceutical preparations can also be carried out according to known pharmaceutical preparations, except as mentioned in the present invention. And, in addition to those mentioned herein, suitable pharmaceutical excipients are known in the art, see for example the 2005 edition handbook of pharmaceutical excipients (fourth edition original works).
In a further embodiment of the present invention, there is provided a compound as described in the first aspect above or a pharmaceutical composition or pharmaceutical formulation as described in the third aspect above for use in the manufacture of a medicament or reagent for inhibiting bruton's tyrosine kinase overexpression.
In a further embodiment of the present invention, there is provided a use of a compound described in the first aspect above, or an isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or pharmaceutical formulation described in the third aspect above, in the manufacture of a medicament for the treatment of a disease associated with bruton's tyrosine kinase overexpression; preferably, the disease is an autoimmune disease, more preferably rheumatoid arthritis.
In a further embodiment of the invention, there is provided a method of treating rheumatoid arthritis, comprising administering to a subject a therapeutically effective amount of a compound according to the first aspect of the invention or a pharmaceutical composition or formulation according to the third aspect of the invention.
The subject of the present invention refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
A therapeutically effective amount according to the present invention is that amount of active compound or pharmaceutical agent, including a compound of the present invention, that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other medical professional, which response includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated.
The range of therapeutically effective amounts that can be used will be known to the researcher, veterinarian, medical doctor or other medical professional in the art based on clinical trials or other means known in the art.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1: synthesis of Compounds W-3 to W-5
Synthesis of intermediate N- (3-bromo-2-methylphenyl) -4- (tert-butyl) benzamide (3b)
Starting material 4(1.00g,5.37mmol) was dissolved in 15mL dry DCM (via ice bath)
Molecular sieve drying), after the reaction system is cooled to 0 ℃, slowly adding the raw material 3a (1.16g,5.91mmol) dropwise, changing the solution from orange yellow to milky suspension, adding DIEA (1.39g,10.75mmol), reacting for 30min in ice bath, and reacting for 2h at normal temperature. TLC monitoring of the reaction completion, add about 1mL saturated NaHCO3The reaction was quenched with a solution, the solvent was evaporated under reduced pressure, diluted with about 50mL of water, extracted with ethyl acetate (15 mL. times.3), and the organic phases were combined, and successively treated with 1N HCl solution (50 mL. times.1) and saturated NaHCO3The solution (50 mL. times.1 times), saturated brine (50 mL. times.1 times) and the organic phase were washed with anhydrous MgSO4Drying for 30min, filtering, distilling under reduced pressure to remove the filtrate to obtain white crude product, and recrystallizing with ethyl acetate-petroleum ether system to obtain white needle-like solid (1.64g, 91% yield).1H NMR(400MHz,Chloroform-d)δ7.85–7.81(m,2H),7.79(s,1H),7.52(d,J＝8.5Hz,2H),7.43(d,J＝8.0Hz,1H),7.10(t,J＝8.0Hz,1H),2.41(s,3H),1.36(s,9H)；ESI-MS,m/z:344.34[M-H]-；C18H20BrNO(345.07)
Synthesis of intermediate 4-methylbenzoyl chloride (4b)
Starting material 4a (1.00g,7.34mmol) was dissolved in 30mL dry DCM (via ice bath)
Molecular sieve drying), after the reaction system is cooled, adding oxalyl chloride (5mL,2.0mol/L in DCM) slowly and dropwise, adding 2 drops of DMF dropwise, bubbling out a large amount of bubbles, and continuing the reaction for about 2 hours under the ice-bath condition. TLC monitoring reaction is finished, stop stirring, low temperature and decompression to remove DCM and excessive oxalyl chloride to obtain colorless liquid which is not further processed due to instability, and directly put into next reaction after being dissolved in anhydrous DCM.
Synthesis of intermediate N- (3-bromo-2-methylphenyl) -4-methylbenzamide (4c)
The same synthesis as intermediate 3b was carried out in the form of a white solid with a yield of 53%.1H NMR(400MHz,Chloroform-d)δ7.78(d,J＝7.9Hz,3H),7.72(s,1H),7.43(d,J＝8.0Hz,1H),7.30(d,J＝7.9Hz,2H),7.10(t,J＝8.0Hz,1H),2.44(s,3H),2.41(s,3H)；ESI-MS,m/z:302.23[M-H]-；C15H14BrNO(303.03)
Synthesis of intermediate N- (3-bromo-2-methylphenyl) -4-ethylbenzamide (5b)
The same synthesis method as the intermediate 3b is adopted, white solid is obtained, and the yield is 99%.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.91(d,J＝8.1Hz,2H),7.53(d,J＝7.9Hz,1H),7.37(d,J＝8.1Hz,2H),7.33(d,J＝7.8Hz,1H),7.17(t,J＝7.9Hz,1H),2.69(q,J＝7.6Hz,2H),2.27(s,3H),1.21(t,J＝7.6Hz,3H)；ESI-MS,m/z:316.45[M-H]-；C16H16BrNO(317.04)
Synthesis of intermediate 4- (tert-butyl) -N- [2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] benzamide (3c)
A50 mL two-necked flask was charged with bis-pinacolato borate (0.18g,0.69mmol), anhydrous potassium acetate (0.17g,1.73mmol), Pd (dppf) Cl2·CH2Cl2(44mg,0.017mmol) connected in sequence with a spherical condenser tube, a three-way valve and an argon balloon, and after the device is installed, vacuumizing and replacing argon for three times; intermediate 3b (0.20g,0.58mmol) was accurately weighed, dissolved in 5mL of ultra dry 1, 4-dioxane, sonicated for 1min and replaced with argon for 30s, this was repeated three times, the solution was injected into the reaction flask, replaced with argon three times, and reacted in an oil bath at 80 ℃ for about 10 h. TLC monitoring reaction completion, diatomaceous earth filtration, washing of filter cake with a small amount of ethyl acetate, evaporation under reduced pressure to remove filtrate, dilution with about 60mL of water, ethyl acetate extraction (15 mL. times.3), combining organic phases, washing with saturated brine (50 mL. times.1), and passing organic phase over anhydrous MgSO4After drying, filtration and concentration gave a yellowish brown oil which was purified by silica gel column chromatography to give a white solid (100mg, 43% yield).1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),7.92(d,J＝8.3Hz,2H),7.55(s,2H),7.53(d,J＝2.2Hz,1H),7.40(s,1H),7.21(t,J＝7.6Hz,1H),2.37(s,3H),1.32(s,12H),1.31(s,9H)；ESI-MS,m/z:394.65[M+H]+；C24H32BNO3(393.35)
Synthesis of intermediate 4- (tert-butyl) -N- [2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] benzamide (4c)
The same synthesis as intermediate 3c, white solid, yield 17%.1H NMR(600MHz,Chloroform-d)δ8.03(d,J＝7.2Hz,1H),7.79(d,J＝8.0Hz,2H),7.68(s,1H),7.64(dd,J＝7.4,1.1Hz,1H),7.30(d,J＝7.9Hz,2H),7.25(d,J＝7.7Hz,1H),2.54(s,3H),2.44(s,3H),1.36(s,12H).ESI-MS,m/z:352.24[M+H]+；C21H26BNO3(351.20)
Synthesis of intermediate 4-ethyl-N- [2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] benzamide (5c)
The same synthesis as intermediate 3c, white solid, yield 30%.1H NMR(600MHz,Chloroform-d)δ8.03(d,J＝7.1Hz,1H),7.82(d,J＝8.0Hz,2H),7.71(s,1H),7.64(dd,J＝7.4,1.1Hz,1H),7.32(d,J＝8.1Hz,2H),7.25(d,J＝7.7Hz,1H),2.73(q,J＝7.6Hz,2H),2.54(s,3H),1.36(s,12H),1.28(t,J＝7.6Hz,3H)；ESI-MS,m/z:366.56[M+H]+；C22H28BNO3(365.22)
Synthesis of intermediate 2, 4-dichloro-7-tosyl-7H-pyrrolo [2,3-d ] pyrimidine (2)
Weighing raw material 1(2.00g,10.64mmol) into a 100mL eggplant-shaped bottle, and adding about 30mL dichloromethane to dissolve the raw material to obtain light green suspension; slowly adding p-methylbenzenesulfonyl chloride (2.23g,11.70mmol) under the ice-bath condition, dropwise adding TEA (2.15g,21.28mmol) after uniformly stirring, then adding a catalytic amount of DMAP, enabling the solution to become clear and then to generate light white filaments, and reacting for 8 hours at room temperature under stirring. TLC monitored the reaction completion, diluted with about 30mL DCM, washed with 1N HCl solution (50 mL. times.1), washed with saturated brine (50 mL. times.1), and the organic phase was washed with anhydrous MgSO4Drying, filtering, evaporating to dryness to obtain light yellow white solid, pulping with petroleum ether, and filtering to obtain white solid (3.43g, 94%)1H NMR(600MHz,DMSO-d6)δ8.12(d,J＝4.1Hz,1H),8.03(d,J＝8.4Hz,2H),7.50(d,J＝8.3Hz,2H),6.98(d,J＝4.1Hz,1H),2.38(s,3H)；ESI-MS,m/z:341.86[M+H]+；C13H9Cl2N3O2S(340.98)
Synthesis of intermediate 2-chloro-N- [4- (4-methylpiperazin-1-yl) phenyl ] -7-tosyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine (3)
Accurately weighing raw material 2(1.50g,4.39mmol) in 100mL of clean dried eggplant-shaped bottle, adding about 20mL of absolute ethyl alcohol, and ultrasonically suspending to obtain milky suspension; after stirring uniformly, 4- (4-methylpiperazin-1-yl) aniline (1.00g,5.26mmol) was added, the solution turned into a brownish black color, and after mixing uniformly, DIPEA (2.00g,13.08mmol) was added, and the mixture was reacted for 5 hours in a 80 ℃ sand bath. TLC monitoring reaction is finished, the mixture is suspended after being cooled, a light purple filter cake is directly obtained by filtration, the filter cake is pulped and purified by cold ethyl acetate, and after filtration, the mixture is dried in vacuum to obtain a white-like solid (1.20g, the yield is 55%).1H NMR(600MHz,DMSO-d6)δ9.86(s,1H),7.96(d,J＝8.4Hz,2H),7.62(s,1H),7.49–7.36(m,4H),6.95(d,J＝9.1Hz,2H),3.18–3.06(m,4H),2.48–2.42(m,4H),2.38(s,3H),2.22(s,3H)；ESI-MS,m/z:497.03[M+H]+；C24H25ClN6O2S(496.14)
Synthesis of the final product 4-Ethyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-5)
Intermediate 5c (50mg,0.14mmol), intermediate 3(68mg,0.14mmol), cesium carbonate (0.14g,0.41mmol), Pd (OAc) were accurately weighed2(31mg,0.14mmol)、PCy3(0.12g,0.42mmol) in 35mL of clean dry microwave reaction tube; about 3mL of ultra-dry DMF subjected to ultrasonic deoxygenation-argon replacement and 1mL of purified water are added, pre-stirred for about 2min, and then reacted for 25min at 140 ℃ by a microwave reaction instrument (standard mode). TLC monitoring reaction is finished, and yellow brown suspension is formed; adding water to increase volume to precipitate off-white insoluble substances, extracting with ethyl acetate methanol mixed solvent (volume ratio of 10:1) (30mL × 3 times), mixing organic phases, washing with saturated saline (50mL × 1 times), and passing the organic phase through anhydrous MgSO4Drying, filtering, concentrating under reduced pressure to obtain white emulsion, and separating and purifying by silica gel column chromatography to obtain white solid (10mg, 10%). 248 ℃ under 246-;1H NMR(600MHz,DMSO-d6)δ11.68(s,1H),9.85(s,1H),9.14(s,1H),7.94(d,J＝8.1Hz,2H),7.69(d,J＝8.9Hz,2H),7.52(d,J＝6.9Hz,1H),7.37(d,J＝8.1Hz,2H),7.36(s,1H),7.28(t,J＝7.7Hz,1H),7.22–7.18(m,1H),6.91(d,J＝9.1Hz,2H),6.71(s,1H),3.10–3.07(m,4H),2.69(q,J＝7.6Hz,2H),2.47–2.44(m,4H),2.34(s,3H),2.22(s,3H),1.22(t,J＝7.6Hz,3H)；13C NMR(151MHz,DMSO-d6)δ165.84,159.91,151.85,148.07,142.36,137.41,132.81,132.63,128.32,128.23,127.14,125.43,122.37,116.16,101.78,99.32,55.16,49.18,46.20,28.55,15.88,15.86；ESI-MS,m/z:546.35[M+H]+；C33H35N7O(545.29)
synthesis of the final product 4-tert-butyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-3)
And (3) obtaining yellow oily matter by the same synthetic method of the final product W-5, dissolving the yellow oily matter in a mixed solution of methanol, water and tetrahydrofuran, adding 3 times of equivalent of LiOH, stirring, adding water, separating out white solid, and separating and purifying by silica gel column chromatography to obtain the white solid with the yield of 12%. m.p. 244-;1H NMR(600MHz,DMSO-d6)δ11.73(s,1H),9.89(s,1H),9.19(s,1H),7.95(d,J＝8.4Hz,2H),7.70(d,J＝8.8Hz,2H),7.56–7.53(m,2H),7.52(dd,J＝7.6,1.2Hz,1H),7.37(d,J＝7.1Hz,1H),7.28(d,J＝7.7Hz,1H),7.23–7.20(m,1H),6.91(d,J＝9.1Hz,2H),6.72(s,1H),3.09(s,4H),2.51(s,4H),2.34(s,3H),2.26(s,3H),1.32(s,9H)；13C NMR(151MHz,DMSO-d6)δ165.34,154.36,153.48,151.33,146.50,136.90,132.56,132.43,131.87,127.91,127.54,126.73,125.22,125.04,122.06,121.73,115.75,101.31,98.84,54.50,48.62,45.48,34.70,30.97,15.48；ESI-MS,m/z:574.40[M+H]+；C35H39N7O(573.32)
synthesis of the final product 4-methyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide (W-4)
The final product W-5 was synthesized as a white solid in 12% yield. m.p. -. 241-;1H NMR(400MHz,DMSO-d6)δ11.70(s,1H),9.86(s,1H),9.16(s,1H),7.93(d,J＝8.1Hz,2H),7.70(d,J＝8.9Hz,2H),7.53(d,J＝6.9Hz,1H),7.35(t,J＝9.0Hz,3H),7.28(t,J＝7.7Hz,1H),7.23–7.19(m,1H),6.91(d,J＝9.0Hz,2H),6.72(s,1H),3.11–3.05(m,4H),2.48–2.43(m,4H),2.39(s,3H),2.34(s,3H),2.22(s,3H)；13C NMR(101MHz,DMSO-d6)δ165.81,153.99,151.81,147.13,142.35,141.91,137.37,133.05,132.80,132.27,129.40,128.36,128.15,127.23,125.48,122.48,122.29,116.16,101.78,99.33,55.15,49.15,46.20,21.49,15.93；ESI-MS,m/z:532.56[M+H]+；C32H33N7O(531.27)
example 2: synthesis of Compound W-2
Synthesis of intermediate 2-chloro-N- [4- (4-methylpiperazin-1-yl) phenyl ] pyrimidin-4-amine (2c)
Accurately weighing the raw material 2a (0.40g,2.68mmol) into a 50mL eggplant-shaped bottle, adding about 10mL absolute ethyl alcohol to dissolve, insolubilizing and ultrasonically treating the mixture to form a white suspension, adding DIEA (0.87g,8.05mmol) into the white suspension, uniformly stirring the mixture, adding the raw material 2b (0.40g,2.23mmol) into a reaction bottle, changing the solution into a brown suspension, and carrying out sand bath reaction at 70 ℃ for 4 hours. TLC is used for monitoring the reaction, standing and cooling are carried out, precipitate is separated out and is directly filtered, a filter cake is washed by a small amount of cold ethanol, and the precipitate is dried in vacuum to obtain a yellow-green solid (0.48g, the yield is 60%).
Synthesis of the final product 4- (tert-butyl) -N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } pyrimidin-2-yl } phenyl } benzamide (W-2)
Accurately weighed intermediate 3c (0.10g,0.25mmol), intermediate 2c (74mg,0.25mmol), cesium carbonate (0.25g,0.25mmol), Pd (OAc)2(23mg,0.10mmol)、PCy3(84mg,0.30mmol) in 35mL of clean dry microwave reaction tube; adding about 2.5mL of ultra-dry DMF subjected to ultrasonic deoxygenation-argon replacement and 0.5mL of purified water, pre-stirring for about 2min to obtain a yellow suspension containing white insoluble substances, and reacting at 140 ℃ for 25min in a standard mode of a microwave reaction instrument. TLC monitoring reaction is finished, and the reaction solution becomes a gray black suspension; adding water to increase volume to precipitate off-white insoluble substances, extracting with ethyl acetate methanol mixed solvent (volume ratio of 10:1) (30mL × 3 times), mixing organic phases, washing with saturated saline (50mL × 1 times), and passing the organic phase through anhydrous MgSO4Drying, filtering, concentrating under reduced pressure to obtain light green color, separating and purifying with silica gel column chromatography to obtain white solid, and recrystallizing with ethyl acetate-petroleum ether system to obtain white solidSolid (32mg, 24% yield). 240 ℃ under 238. p. -;1H NMR(600MHz,DMSO-d6)δ9.90(s,1H),9.43(s,1H),8.31(d,J＝5.9Hz,1H),7.94(d,J＝8.4Hz,2H),7.55(d,J＝8.5Hz,2H),7.51–7.45(m,3H),7.39(d,J＝7.1Hz,1H),7.30(t,J＝7.7Hz,1H),6.91(d,J＝9.0Hz,2H),6.63(d,J＝6.0Hz,1H),3.07(s,4H),2.44(s,4H),2.29(s,3H),2.21(s,3H),1.32(s,10H)；13C NMR(151MHz,DMSO-d6)δ165.35,154.41,140.82,137.01,132.59,131.76,127.53,125.23,115.91,48.61,34.70,30.97,15.35；ESI-MS,m/z:536.26[M+H]+,m/z:1069.89[2M+H]+；C33H38N6O(534.31)
example 3: synthesis of the end product W-19
Synthesis of intermediate 4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carbonyl chloride (19b)
The intermediate 4b was synthesized as a pale yellow solid without further treatment, dissolved in anhydrous DCM and directly subjected to the next reaction. C9H9ClOS(200.01)
Synthesis of intermediate N- (3-bromo-2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carboxamide (19c)
The same synthesis as intermediate 3b, white solid, yield 80%.1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),7.71(s,1H),7.51(d,J＝7.9Hz,1H),7.29(d,J＝7.8Hz,1H),7.16(t,J＝7.9Hz,1H),2.75(t,J＝5.4Hz,2H),2.60(t,J＝5.4Hz,2H),2.25(s,3H),1.82–1.71(m,4H)；ESI-MS,m/z:348.23[M-H]-；C16H16BrNOS(349.01)
Synthesis of intermediate N- (2-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carboxamide (19d)
The same synthesis as intermediate 3c, a white-like solid, with a yield of 49%.1H NMR(600MHz,Chloroform-d)δ8.00(d,J＝7.9Hz,1H),7.61(dd,J＝7.4,1.2Hz,1H),7.47(s,1H),7.31(s,1H),7.23(t,J＝7.7Hz,1H),2.81(t,J＝6.1Hz,2H),2.64(t,J＝6.1Hz,2H),2.52(s,3H),1.89–1.85(m,2H),1.82(m,J＝8.2,3.1,2.6Hz,2H),1.35(s,12H)；ESI-MS,m/z:398.42[M+H]+；C22H28BNO3S(397.19)
Synthesis of the final product N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carboxamide (W-19)
The dichloromethane-petroleum ether system is recrystallized to obtain white solid with the yield of 60 percent by the same synthetic method of the final product W-5. m.p. 200-;1H NMR(600MHz,DMSO-d6)δ9.61–9.53(m,2H),9.38(s,1H),7.69(dd,J＝7.4,1.5Hz,1H),7.64–7.56(m,3H),7.50–7.41(m,2H),7.12(dd,J＝8.4,7.3Hz,1H),6.95–6.90(m,2H),6.88(d,J＝7.6Hz,1H),3.17(t,J＝7.1Hz,4H),2.82–2.76(m,2H),2.73(t,J＝6.9Hz,2H),2.61(t,J＝7.0Hz,4H),2.38(s,2H),2.27(s,2H),1.83–1.68(m,4H)；13C NMR(151MHz,DMSO-d6)δ162.53,158.16,153.98,152.15,145.65,143.36,137.25,136.94,135.36,135.17,134.26,129.44,125.39,125.10,125.03,124.82,124.19,122.17,115.01,107.13,100.29,54.04,48.81,44.57,27.06,25.13,23.05,22.84,13.45；ESI-MS,m/z:578.24[M+H]+；C33H35N7OS(577.26)
example 4: ramos cell proliferation inhibition experiments by compounds shown in general formula (I) and general formula (II)
Cell Counting Kit-8(CCK-8) method is adopted to detect anti-Cell proliferation activity, WST-8 can be reduced into water-soluble Formazan (Formazan) by succinate dehydrogenase in mitochondria of living cells in the presence of an electronic coupling reagent 1-Methoxy-5-methylphenazinyl methyl sulfate (1-Methoxy PMS), and the Formazan is dissolved in culture medium and shows orange color. Formazan formation is proportional to the number of living cells in a range of cell numbers, and thus the number of living cells was determined by measuring the OD at 450 nm.
Taking Ramos cells in logarithmic growth phase, counting the cells, and adjusting the cell suspension density to 1.5 multiplied by 105one/mL.
And adding 100 mu L of the uniformly mixed cell suspension to a transparent 96-well plate along the wall of the hole, adding 100 mu L of PBS to each hole in the outermost circle of the 96-well plate in order to avoid edge effect, and stabilizing in an incubator for 2 hours.
Gradient dilution of compound stock solution with culture medium to concentration of 6.25-200. mu.M, adding 10. mu.L of compound per well, and gently tapping the plate to help mix; each compound was set at 6 concentrations, 5 secondary wells were set at each concentration, and a 100% control without compound and a blank control without compound and without cells were set. (first experiment setup 0.01% DMSO group and drug absorption group with Compound and Medium only)
37℃、5％CO2And culturing for 24 hours in an incubator with 95% humidity.
Adding 10 mu L of CCK-8 solution into each well along the wall of the well under the condition of keeping out of the light, gently knocking to help mixing uniformly, and continuously incubating for 4 hours in an incubator under the condition of keeping out of the light.
The absorbance values at 450nm and 650nm were measured using a multimode microplate detection system. The cell viability was calculated as follows:
calculating the proliferative toxicity of the compound to Ramos cells at the concentration of 10 mu M by a formula, selecting a more optimized compound to calculate the proliferative toxicity of the compound at different concentrations to Ramos cells, fitting a curve by utilizing GraphPad Prism 8, and passing through [ inhibitor [ ]]vs. normalized response-Variable Slope analysis IC of the calculated Compounds50The value is obtained.
Inhibition of Ramos cell proliferation by Compounds of Table 1 at 10. mu.M concentration
Ramos cells with high expression of BTK are selected, and an anti-proliferation activity experiment is carried out on a target compound. The experimental result shows that the activity is improved by the structural modification of the solvent exposure area; the hinge region introduces a fused heterocycle to reduce the activity; pocket region R1When the compound is substituted by an electron-withdrawing group, the activity is better; when X is sulfonamide, the activity is better. Subsequently, we selected the compound W-10 with the best inhibition rate and determined the IC of the antiproliferative activity of the compound on Ramos cells50IC thereof50The value was 21. mu.M, which is superior to the positive drug.
Example 5: w-10 compound shown in the general formula (I) is used for testing the toxicity of hBMC
As the designed compound is used for treating non-life threatening diseases such as rheumatoid arthritis, the toxicity of the compound to lymphocytes of normal people is tested, and the toxicity of the compound to hPBMC is verified by combining trypan blue staining microscopic counting and a CCK-8 method.
After culturing for about 48 hours, the cells were observed to be in good condition under an inverted microscope.
According to the literature, the cell suspension is adjusted to 3X 10 after cell counting5one/mL.
The experiments were divided into two groups, and performed in 96-well and 24-well plates, respectively. For a 96-well plate, 100. mu.L of the mixed cell suspension was added per well. For a 24-well plate, approximately 500. mu.L of the homogenized cell suspension was added per well. 37 ℃ and 5% CO2And the 95% humidity incubator is stabilized for about 1 hour.
Compound stocks were diluted in media at a gradient concentration of 6.25. mu.M to 200. mu.M, 10. mu.L of compound was added to each well of a 96-well plate (50. mu.L to each well of a 24-well plate), and the plate was gently tapped to aid in mixing. Compound W-10 was set at 6 concentrations, 5 sub-wells per concentration (1 sub-well for 24-well plates), and 100% control and blank control without compound were set.
37℃、5％CO2And culturing for 48 hours in an incubator with 95% humidity.
For 96-well plates, 10. mu.L of CCK-8 solution was added to each well along the walls of the well in the dark, gently tapped to aid mixing, 5% CO at 37 ℃2Incubate for 4h, and detect absorbance values at 450nm and 650nm using a microplate reader. The calculation formula is as follows,
for 24-well plates, mix well by gentle pipetting, add about 10uL of filtered trypan blue solution to 100 uL of cell suspension, and stain for 5 min. 10 μ L of the stained cells were aspirated, counted by a counter, and the cell survival rate was calculated, thereby calculating the number of viable cells.
Because the designed compound is suitable for non-life-threatening diseases such as rheumatoid arthritis and the like and needs to be taken for a long time, the optimized compound W-10 is selected and the toxicity to normal lymphocytes is measured. The experimental result shows that the toxicity of the compound W-10 to normal lymphocytes is lower than that of a positive drug within 12 mu M concentration, and the cell activity is maintained to be more than 80%; when the concentration of the compound is increased to 25 mu M or above, the toxicity to normal lymphocytes is increased, and the cell activity is obviously reduced.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A compound having the general structural formula shown in formula (I):
wherein R is1Selected from different electron withdrawing or donating groups; r2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide;
the compounds also include pharmaceutically acceptable salts, stereoisomers, isotopic labels, solvates, polymorphs, or prodrugs thereof.
2. The compound of claim 1, wherein R is1Is any one of 4-methyl, 4-ethyl, 4-trifluoromethyl, 4-isopropyl, 4-cyclopropyl, 4-methoxy, 4-tert-butyl, 4-dimethylamino, 4-cyano, 2, 4-dimethyl, 3-trifluoromethyl and 2-fluoro-4-trifluoromethyl.
3. The compound of claim 1, having the structure of formula (II):
wherein, R is2Any one selected from methyl, cyano, hydrogen atom and fluorine atom; x is any one of amide, ester and sulfonamide.
4. A compound according to any one of claims 1 to 3, wherein the compound comprises:
4-tert-butyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-methyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-ethyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide;
4-isopropyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-methoxy-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-cyclopropyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-dimethylamino-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
4-cyano-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
2, 4-dimethyl-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzamide;
2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyridin-2-yl } -N- [4- (trifluoromethyl) phenyl ] benzamide;
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -3- (trifluoromethyl) benzamide;
2-fluoro-N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide;
n- { 2-methyl-3- {4- [ (4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzenesulfonamide;
4- (tert-butyl) -N- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } benzenesulfonamide;
2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl-4-benzoic acid tert-butyl ester;
n- { 2-methyl-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4,5,6, 7-tetrahydrobenzo [ b ] thiophene-2-carboxamide;
n- {3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide;
n- { 2-fluoro-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide;
n- { 2-cyano-3- {4- { [4- (4-methylpiperazin-1-yl) phenyl ] amino } -7H-pyrrolo [2,3-d ] pyrimidin-2-yl } phenyl } -4- (trifluoromethyl) benzamide.
5. A process for the preparation of a compound according to any one of claims 1 to 4, characterized in that it comprises:
a) when the compound is a compound shown as a formula (I) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
(ii) a Or,
b) when the compound is a compound shown as a formula (II) and pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polycrystal or prodrug thereof, the synthetic route is as follows:
6. a pharmaceutical composition comprising a compound according to any one of claims 1 to 4.
7. Pharmaceutical preparation, characterized in that it comprises a compound according to any one of claims 1 to 4 and at least one pharmaceutically acceptable adjuvant and/or carrier.
8. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 or a pharmaceutical formulation according to claim 7 in the manufacture of a medicament or agent for inhibiting bruton's tyrosine kinase overexpression.
9. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 or a pharmaceutical formulation according to claim 7 in the manufacture of a medicament for the treatment of a disease associated with bruton's tyrosine kinase overexpression; preferably, the disease is an autoimmune disease, more preferably rheumatoid arthritis.
10. A method of treating rheumatoid arthritis comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 or a pharmaceutical formulation according to claim 7.
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| WO2006017443A2 (en) * | 2004-08-02 | 2006-02-16 | Osi Pharmaceuticals, Inc. | Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds |
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| WO2009016132A1 (en) * | 2007-07-27 | 2009-02-05 | Janssen Pharmaceutica Nv | Pyrrolopyrimidines |
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| CN111620878A (en) * | 2020-06-10 | 2020-09-04 | 中国药科大学 | Pyrrolopyrimidine derivatives as protein kinase inhibitors and application thereof |
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| WO2006017443A2 (en) * | 2004-08-02 | 2006-02-16 | Osi Pharmaceuticals, Inc. | Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds |
| CN101052629A (en) * | 2004-08-02 | 2007-10-10 | Osi制药公司 | Aryl-amino substituted pyrrolopyrimidine multi-kinase inhibiting compounds |
| WO2009016132A1 (en) * | 2007-07-27 | 2009-02-05 | Janssen Pharmaceutica Nv | Pyrrolopyrimidines |
| CN104662024A (en) * | 2012-10-26 | 2015-05-27 | 弗·哈夫曼-拉罗切有限公司 | Inhibitors of bruton's tyrosine kinase |
| CN111620878A (en) * | 2020-06-10 | 2020-09-04 | 中国药科大学 | Pyrrolopyrimidine derivatives as protein kinase inhibitors and application thereof |
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